Is VAMP2 p.Ser75Pro (c.223T>C) pathogenic?

VAMP2 p.Ser75Pro (c.223T>C) is classified Pathogenic in VAMP2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-01-31). AlphaMissense: likely pathogenic (0.9987); Absent from gnomAD v4.1; Associated with neurodevelopmental disorder with hypotonia and autistic features with or without hyperkinetic movements.

How common is VAMP2 p.Ser75Pro (c.223T>C) in the general population?

VAMP2 p.Ser75Pro (c.223T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about VAMP2 p.Ser75Pro (c.223T>C)?

AlphaMissense predicts likely pathogenic (score 0.9987) — an in-silico prediction, not a clinical call.

VAMP2 p.Ser75Pro

Q: What condition is associated with VAMP2 p.Ser75Pro (c.223T>C)?

VAMP2 p.Ser75Pro (c.223T>C) is associated with neurodevelopmental disorder with hypotonia and autistic features with or without hyperkinetic movements (ClinVar).

c.223T>C · rs1598265387 · VCV810675

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9987 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.9987	likely pathogenic ✓ concordant with ClinVar · top 4% in VAMP2
REVEL	0.573	indeterminate
SaProt	LLR -16.56	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
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	31.0	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.Ser75Pro
Coding: c.223T>C
MANE Select: NM_014232
dbSNP: rs1598265387
Type: single nucleotide variant
Location: chr17:8161667 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.34 · 7 PDB
Residue 75: a UniProt-annotated variant site (in nedhahm; impaired vesicle fusion); an α-helix; the v-snare coiled-coil homology domain

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.Phe77Ser 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-ser75pro (accessed [today's date]).

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