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RPH3A – Neurodevelopmental Disorder

RPH3A encodes Rabphilin-3A, a synaptic protein that stabilizes the GluN2A subunit of N-methyl-D-aspartate (NMDA) receptors, critical for synaptic plasticity and cognition. Heterozygous missense variants in RPH3A have been linked to a variable neurodevelopmental disorder ranging from drug-resistant epilepsy to high-functioning autism spectrum disorder (MONDO:0700092).

Clinical Validity

The association between RPH3A and neurodevelopmental disorder is classified as Moderate. Six unrelated probands harbor de novo heterozygous missense variants (PMID:37403762) with consistent phenotypes and supportive functional assays demonstrating altered NMDA receptor function.

Genetic Evidence

Inheritance is Autosomal dominant, with six de novo cases (PMID:37403762). No multiplex families have been reported (affected relatives: 0). All variants are missense substitutions affecting conserved residues within regions that interact with NMDA receptors, with consistent phenotypes across probands.

Functional / Experimental Evidence

In vitro studies in rat hippocampal neuronal cultures show that RPH3A missense variants (e.g., p.Thr450Ser, p.Asn618Ser) reduce synaptic localization yet increase surface levels and currents of GluN2A-containing NMDA receptors, alter postsynaptic calcium signaling, and affect dendritic spine morphology (PMID:37403762). An independent study confirmed presynaptic glutamate release deficits and reduced NMDAR retention for p.Arg209Lys and p.Gln508His (PMID:40082528), consistent with a gain-of-function mechanism.

Conflicting Evidence

No studies to date have provided evidence refuting or substantially disputing the RPH3A–neurodevelopmental disorder association.

Conclusion

Collectively, six de novo missense RPH3A variants in unrelated individuals with concordant functional data support a Moderate gene-disease relationship. RPH3A variant screening should be considered in patients with unexplained epilepsy or autism spectrum presentations.

References

  • Genetics in Medicine • 2023 • Missense variants in RPH3A cause defects in excitatory synaptic function and are associated with a clinically variable neurodevelopmental disorder. PMID:37403762
  • Scientific Reports • 2025 • Arg209Lys and Gln508His missense variants in Rabphilin 3A cause pre- and post-synaptic dysfunctions at excitatory glutamatergic synapses. PMID:40082528

Evidence Based Scoring (AI generated)

Gene–Disease Association

Moderate

6 de novo probands identified in unrelated individuals (PMID:37403762) with concordant functional data

Genetic Evidence

Moderate

Six heterozygous missense variants in unrelated cases with consistent phenotype (PMID:37403762)

Functional Evidence

Moderate

Neuronal culture and electrophysiological assays demonstrate gain-of-function on NMDA receptor localization and currents (PMID:37403762; PMID:40082528)