SH3GL2

Chr 9

SH3 domain containing GRB2 like 2, endophilin A1

Also known as: CNSA2, EEN-B1, SH3D2A, SH3P4

NCBI Gene: 6456 ENSG00000107295 UniProt: Q99962 OMIM: 604465

The SH3GL2 protein mediates synaptic vesicle endocytosis and is required for BDNF-dependent dendrite outgrowth, playing a critical role in synaptic function and neuronal development. Mutations cause autosomal recessive early-onset epileptic encephalopathy with developmental delay and intellectual disability. The gene is highly constrained against loss-of-function variants, indicating that complete loss of protein function is likely pathogenic.

OMIM ResearchSummary from RefSeq, UniProt

Enables identical protein binding activity. Involved in negative regulation of blood-brain barrier permeability; negative regulation of gene expression; and negative regulation of signal transduction. Located in perinuclear region of cytoplasm. Implicated in Parkinson's disease. [provided by Alliance of Genome Resources, Jun 2026]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.79

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.79LOEUF

pLI 0.000

Z-score 2.30

OE 0.47 (0.29–0.79)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.96Z-score

OE missense 0.80 (0.70–0.92)

153 obs / 190.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.47 (0.29–0.79)

0≤0.351.4

Missense OE?0.80 (0.70–0.92)

0≤0.61.4

Synonymous OE?1.32

0≤1.21.6

LoF obs/exp: 10 / 21.5Missense obs/exp: 153 / 190.4Syn Z: -2.04

Background carrier burden — how many people carry a rare variant somewhere in SH3GL2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 290

448 rare PASS variants

Rare truncating (LoF)

1 in 7,100

38 rare PASS variants

Rare synonymous (reference)

1 in 140

208 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SH3GL2. 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 330	1 in 5,300
South Asian	~43k	1 in 130	≈ 1 in 14,000
Remaining (unassigned)	~30k	1 in 160	≈ 1 in 15,000
European (Finnish)	~27k	1 in 2,700	≈ 1 in 13,000
Admixed American	~22k	1 in 110	≈ 1 in 11,000
African / African American	~21k	1 in 170	≈ 1 in 17,000
East Asian	~20k	1 in 230	≈ 1 in 17,000
Ashkenazi Jewish	~13k	1 in 400	none seen
Middle Eastern	~2,884	1 in 190	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.

Exome coverage (gnomAD): 7 of 9 coding exons well covered in gnomAD exomes; exons 2, 3 marginal. Genomes: all 9.? see exons ↓