Is GSN p.Met726Val (c.2176A>G) pathogenic?

GSN p.Met726Val (c.2176A>G) is classified Uncertain significance in GSN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-01). AlphaMissense: likely benign (0.1122); Very rare (popmax 0.000339%, nfe).

How common is GSN p.Met726Val (c.2176A>G) in the general population?

GSN p.Met726Val (c.2176A>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about GSN p.Met726Val (c.2176A>G)?

AlphaMissense predicts likely benign (score 0.1122) — an in-silico prediction, not a clinical call.

GSN p.Met726Val

c.2176A>G · rs1460889014 · VCV2987026

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1122 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1122	likely benign
REVEL	0.071	moderately benign-leaning
SaProt	LLR -4.95	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.63	GERP -3.8
Regional constraint	o/e 0.87	unconstrained · MANE · 31 kb · p 8.7e-05 · regional, not allelic
Overall
CADD	5.842	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM M777V vs ClinVar M726V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,956 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,902 alleles · very rare exomes 4/1,461,676 · genomes 0/152,226 · joint denominator

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: GSN
Protein: p.Met726Val
Coding: c.2176A>G
MANE Select: NM_198252
dbSNP: rs1460889014
Type: single nucleotide variant
Location: chr9:121332583 (GRCh38)
Gene constraint: LOEUF 0.788 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.76 · 65 PDB
Residue 777 UniProt numbering: the 'actin-binding, ca-sensitive' region; an α-helix

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

Similar variants

GSN p.Asn160Lys Pathogenic ★★ same type
GSN p.Asp163Asn Pathogenic/Likely pathogenic ★★ same type
GSN p.Asp163Tyr Pathogenic/Likely pathogenic ★★ same type
GSN c.1762+2T>C Uncertain significance ★★ same type
GSN c.513+1G>A Uncertain significance ★★ same type
GSN c.753+1G>A Uncertain significance ★★ same type
GSN c.754-1G>T Uncertain significance ★★ same type
GSN c.-9-1981C>T 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/gsn-p-met726val (accessed [today's date]).

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