SNAP91

Chr 6

synaptosome associated protein 91

Also known as: AP180, CALM

NCBI Gene: 9892 ENSG00000065609 UniProt: O60641 OMIM: 607923

The protein functions as a clathrin adaptor that links clathrin to receptors in coated vesicles and regulates clathrin-dependent endocytosis at synapses. Mutations cause autosomal recessive developmental and epileptic encephalopathy with movement abnormalities. This gene is extremely intolerant to loss-of-function variants, indicating that heterozygous variants are unlikely to be pathogenic in most cases.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable several functions, including clathrin adaptor activity; clathrin heavy chain binding activity; and phosphatidylinositol binding activity. Acts upstream of or within regulation of clathrin-dependent endocytosis. Predicted to be located in cytosol; postsynaptic density; and presynaptic membrane. Predicted to be active in several cellular components, including Schaffer collateral - CA1 synapse; cytoplasmic vesicle; and parallel fiber to Purkinje cell synapse. Predicted to be extrinsic component of presynaptic endocytic zone membrane. Biomarker of Alzheimer's disease. [provided by Alliance of Genome Resources, Apr 2025]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.19

Clinical Summary— SNAP91

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

108 VUS of 127 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.19LOEUF

pLI 1.000

Z-score 5.44

OE 0.07 (0.03–0.19)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.16Z-score

OE missense 0.72 (0.65–0.79)

327 obs / 456.8 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.07 (0.03–0.19)

0≤0.351.4

Missense OE?0.72 (0.65–0.79)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 3 / 40.2Missense obs/exp: 327 / 456.8Syn Z: 1.16

This gene — mechanism propensity

0.2997th %ile

GOF

0.3689th %ile

LOF

0.66top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.19

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

127 submitted variants in ClinVar

ClinVar

Classification Summary

VUS108

Likely Benign4

Benign8

108

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	1	106	1	0	108
Likely Benign	0	2	0	2	4
Benign	0	1	2	5	8
Total	1	109	3	7	120

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap SNAP91 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →