Is ACTN1 p.Val211Met (c.631G>A) pathogenic?

ACTN1 p.Val211Met (c.631G>A) is classified Uncertain significance in ACTN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-10). AlphaMissense: likely pathogenic (0.6618); Ultra-rare (popmax 0.0133%, amr); Associated with Inborn genetic diseases.

What condition is associated with ACTN1 p.Val211Met (c.631G>A)?

ACTN1 p.Val211Met (c.631G>A) is associated with Inborn genetic diseases (ClinVar).

How common is ACTN1 p.Val211Met (c.631G>A) in the general population?

ACTN1 p.Val211Met (c.631G>A) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about ACTN1 p.Val211Met (c.631G>A)?

AlphaMissense predicts likely pathogenic (score 0.6618) — an in-silico prediction, not a clinical call.

ACTN1 p.Val211Met

c.631G>A · rs770793826 · VCV2371387

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6618 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6618	likely pathogenic
REVEL	0.853	moderately pathogenic-leaning
SaProt	LLR -11.59	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 7.7	phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 32 kb · p 3.7e-34 · regional, not allelic
Overall
CADD	29.9	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% Admixed American · 8/59,996 alleles

Filtering AF 0.00661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.000991% 16/1,613,902 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,500
Remaining individualsnot grpmax-eligible	0.0016%	62,478
African / African-American	0.00133%	74,908
South Asian	0.0011%	91,078
European (non-Finnish)	0.000424%	235,993

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: ACTN1
Protein: p.Val211Met
Coding: c.631G>A
MANE Select: NM_001130004
dbSNP: rs770793826
Type: single nucleotide variant
Location: chr14:68904700 (GRCh38)
Gene constraint: LOEUF 0.331 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.39 · 4 PDB
Residue 211: the calponin-homology (ch) 2 domain; an α-helix; the 'actin-binding' region

Full ACTN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACTN1 p.Ala48Val Uncertain significance ★★ ⚠ same condition
ACTN1 p.Arg475His Uncertain significance ★★ same condition
ACTN1 p.Asn824Ser Uncertain significance ★★ ⚠ same condition
ACTN1 p.Asp11Asn Uncertain significance ★★ ⚠ same condition
ACTN1 p.Asp868Asn Uncertain significance ★★ ⚠ same condition
ACTN1 p.Asp868Gly Uncertain significance ★★ ⚠ same condition
ACTN1 p.Glu273Lys Uncertain significance ★★ ⚠ same condition
ACTN1 p.Glu423Gly 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/actn1-p-val211met (accessed [today's date]).

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