SH3GL3

Chr 15

SH3 domain containing GRB2 like 3, endophilin A3

Also known as: CNSA3, EEN-B2, HsT19371, SH3D2C, SH3P13

NCBI Gene: 6457 ENSG00000140600 UniProt: Q99963 OMIM: 603362

The protein functions in endocytosis and membrane curvature sensing, recruiting proteins to highly curved membranes and localizing to synaptic endosomes. Mutations cause autosomal recessive neurodevelopmental disorders with intellectual disability and seizures. The gene is highly constrained against loss-of-function variants (pLI = 1.0, LOEUF = 0.80), indicating intolerance to protein loss.

OMIM ResearchSummary from RefSeq, UniProt

Enables identical protein binding activity. Predicted to be involved in central nervous system development and signal transduction. Predicted to be located in acrosomal vesicle and early endosome membrane. Predicted to be part of early endosome. Predicted to be active in several cellular components, including glutamatergic synapse; postsynaptic density, intracellular component; and postsynaptic endosome. [provided by Alliance of Genome Resources, Apr 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.80

Clinical Summary— SH3GL3

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

37 VUS of 41 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.80LOEUF

pLI 0.000

Z-score 2.24

OE 0.47 (0.29–0.80)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.21Z-score

OE missense 0.75 (0.65–0.86)

138 obs / 184.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.47 (0.29–0.80)

0≤0.351.4

Missense OE?0.75 (0.65–0.86)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 10 / 21.1Missense obs/exp: 138 / 184.0Syn Z: -0.76

This gene — mechanism propensity

0.76top 25%

GOF

0.7127th %ile

LOF

0.2581th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

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

41 submitted variants in ClinVar

ClinVar

Classification Summary

VUS37

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	37	37
Likely Benign	0	0
Benign	0	0
Total	37	37

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

33 pathogenic / likely-pathogenic (of 42) ClinVar copy-number / structural variants overlap SH3GL3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →