Is SYN2 p.Val183Met (c.547G>A) pathogenic?

SYN2 p.Val183Met (c.547G>A) is classified Uncertain significance in SYN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: ambiguous (0.4055); Very rare (popmax 0.00668%, eas).

How common is SYN2 p.Val183Met (c.547G>A) in the general population?

SYN2 p.Val183Met (c.547G>A) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about SYN2 p.Val183Met (c.547G>A)?

AlphaMissense predicts ambiguous (score 0.4055) — an in-silico prediction, not a clinical call.

SYN2 p.Val183Met

c.547G>A · rs548591048 · VCV2262376

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4055 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4055	ambiguous
REVEL	0.66	pathogenic-leaning
SaProt	LLR -12.72	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 186 kb · p 0.66 · 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

Grpmax group 0.00668% East Asian · 3/44,898 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.0013% 21/1,613,868 alleles · very rare exomes 16/1,461,650 · genomes 5/152,218 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,966
South Asian	0.00329%	30,362
African / African-American	0.00133%	74,934
European (non-Finnish)	0.00119%	84,277

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.Val183Met
Coding: c.547G>A
MANE Select: NM_133625
dbSNP: rs548591048
Type: single nucleotide variant
Location: chr3:12145698 (GRCh38)
Gene constraint: LOEUF 0.539 · pLI 0.90 (gnomAD)
Structure: AlphaFold pLDDT 75.24
Residue 183: 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-val183met (accessed [today's date]).

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