SH3RF1
Chr 4SH3 domain containing ring finger 1
Also known as: POSH, RNF142, SH3MD2
The protein functions as an E3 ubiquitin ligase involved in protein sorting at the trans-Golgi network and acts as a scaffold protein coordinating JNK signaling pathway components, playing a crucial role in neocortical neuron migration during brain development. Mutations cause autosomal recessive intellectual disability with neuronal migration defects. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.505), consistent with recessive inheritance where heterozygous carriers are typically unaffected.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
More LoF-intolerant than ~75% of genes
Mild missense constraint
The highest-scoring mechanism for this gene is dominant-negative.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
182 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 0 | 53 | 0 | 53 |
Likely Pathogenic | 0 | 0 | 3 | 0 | 3 |
VUS | 0 | 98 | 8 | 0 | 106 |
Likely Benign | 0 | 5 | 0 | 0 | 5 |
Benign | 0 | 1 | 0 | 1 | 2 |
| Total | 0 | 104 | 64 | 1 | 169 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
SH3RF1 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools