Is VAMP2 p.Phe77Ser (c.230T>C) pathogenic?

VAMP2 p.Phe77Ser (c.230T>C) is classified Pathogenic in VAMP2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-01-31). AlphaMissense: likely pathogenic (0.9995); Absent from gnomAD v4.1; Associated with neurodevelopmental disorder with hypotonia and autistic features with or without hyperkinetic movements.

How common is VAMP2 p.Phe77Ser (c.230T>C) in the general population?

VAMP2 p.Phe77Ser (c.230T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about VAMP2 p.Phe77Ser (c.230T>C)?

AlphaMissense predicts likely pathogenic (score 0.9995) — an in-silico prediction, not a clinical call.

VAMP2 p.Phe77Ser

Q: What condition is associated with VAMP2 p.Phe77Ser (c.230T>C)?

VAMP2 p.Phe77Ser (c.230T>C) is associated with neurodevelopmental disorder with hypotonia and autistic features with or without hyperkinetic movements (ClinVar).

c.230T>C · rs1598265384 · VCV810677

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9995 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder with hypotonia and autistic features with or without hyperkinetic movements

Computational evidence

Protein change
AlphaMissense	0.9995	likely pathogenic ✓ concordant with ClinVar · top 2% in VAMP2
REVEL	0.818	moderately pathogenic-leaning
SaProt	LLR -13.70	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.23	constrained · MANE · 653 bp · p 4.2e-11 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: VAMP2
Protein: p.Phe77Ser
Coding: c.230T>C
MANE Select: NM_014232
dbSNP: rs1598265384
Type: single nucleotide variant
Location: chr17:8161660 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.34 · 7 PDB
Residue 77: a functional site ((microbial infection) cleavage; by c.tetani toxin (tetx)); a UniProt-annotated variant site (in nedhahm); an α-helix; the v-snare coiled-coil homology domain; a functional site ((microbial infection) cleavage; by c.botulinum neurotoxin type d (bont/d, botd))

Full VAMP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodevelopmental disorder with hypotonia and autistic features with or without hyperkinetic movements — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

VAMP2 p.Ala74Val Uncertain significance ★★ ⚠ same condition
VAMP2 c.334+12G>C Benign ★★ same condition
VAMP2 p.Gln76Ter Likely pathogenic ★ same condition
VAMP2 p.Val50Met Likely pathogenic ★ same condition
VAMP2 p.Glu78Ala Pathogenic same condition
VAMP2 p.Ser75Pro Pathogenic same condition
VAMP2 c.128_130del Pathogenic ★ same condition
VAMP2 p.Lys59del Uncertain significance ★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/vamp2-p-phe77ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown