Is SYN2 p.Met277Val (c.829A>G) pathogenic?

SYN2 p.Met277Val (c.829A>G) is classified Uncertain significance in SYN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-05). AlphaMissense: likely benign (0.1476); Ultra-rare (popmax 0.0167%, amr).

How common is SYN2 p.Met277Val (c.829A>G) in the general population?

SYN2 p.Met277Val (c.829A>G) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about SYN2 p.Met277Val (c.829A>G)?

AlphaMissense predicts likely benign (score 0.1476) — an in-silico prediction, not a clinical call.

SYN2 p.Met277Val

c.829A>G · VCV4178480

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1476 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1476	likely benign
REVEL	0.554	indeterminate
SaProt	LLR -13.05	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 2.2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 186 kb · p 0.66 · regional, not allelic
Overall
CADD	23.1	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

Grpmax group 0.0167% Admixed American · 10/60,010 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.000744% 12/1,613,932 alleles · ultra-rare exomes 9/1,461,692 · genomes 3/152,240 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	6,001
African / African-American	0.00267%	37,472

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SYN2
Protein: p.Met277Val
Coding: c.829A>G
MANE Select: NM_133625
Type: single nucleotide variant
Location: chr3:12161600 (GRCh38)
Gene constraint: LOEUF 0.539 · pLI 0.90 (gnomAD)
Structure: AlphaFold pLDDT 75.24
Residue 277: the 'c; actin-binding and synaptic-vesicle binding' region

Full SYN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SYN2 p.Ala54Val Benign ★★ same type
SYN2 p.Thr506Ala Benign ★★ same type
SYN2 c.1369+21G>C Uncertain significance ★ same type
SYN2 p.Ala302Gly Uncertain significance ★ same type
SYN2 p.Ala546Gly Uncertain significance ★ ⚠ same type
SYN2 p.Arg179Gln Uncertain significance ★ ⚠ same type
SYN2 p.Arg186Gln Uncertain significance ★ ⚠ same type
SYN2 p.Arg315Trp Uncertain significance ★ ⚠ same type

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/syn2-p-met277val (accessed [today's date]).

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