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

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.

ResearchSummary from RefSeq, UniProt

Enables identical protein binding activity. Predicted to be involved in endocytosis and membrane organization. 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 cytosol; glutamatergic synapse; and presynapse. [provided by Alliance of Genome Resources, Jun 2026]

ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.80

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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

Background carrier burden — how many people carry a rare variant somewhere in SH3GL3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 260

414 rare PASS variants

Rare truncating (LoF)

1 in 1,900

75 rare PASS variants

Rare synonymous (reference)

1 in 320

176 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SH3GL3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 320	1 in 1,800
South Asian	~43k	1 in 150	1 in 2,900
Remaining (unassigned)	~30k	1 in 250	1 in 2,700
European (Finnish)	~27k	1 in 740	1 in 3,300
Admixed American	~22k	1 in 150	1 in 1,900
African / African American	~21k	1 in 200	1 in 1,300
East Asian	~20k	1 in 210	1 in 1,800
Ashkenazi Jewish	~13k	1 in 650	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 210	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.