Is ACTN3 p.Glu856Val (c.2567A>T) pathogenic?

ACTN3 p.Glu856Val (c.2567A>T) is classified Benign in ACTN3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-01-06). AlphaMissense: likely benign (0.2412); Low-frequency (popmax 2.18%, afr); Associated with ACTN3-related disorder.

What condition is associated with ACTN3 p.Glu856Val (c.2567A>T)?

ACTN3 p.Glu856Val (c.2567A>T) is associated with ACTN3-related disorder (ClinVar).

How common is ACTN3 p.Glu856Val (c.2567A>T) in the general population?

ACTN3 p.Glu856Val (c.2567A>T) is low-frequency (popmax 2.18%, afr) (gnomAD).

What do computational predictors say about ACTN3 p.Glu856Val (c.2567A>T)?

AlphaMissense predicts likely benign (score 0.2412) — an in-silico prediction, not a clinical call.

ACTN3 p.Glu856Val

c.2567A>T · rs115296201 · VCV3033080

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2412 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.18%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt

Conditions

ACTN3-related disorder

Computational evidence

Protein change
AlphaMissense	0.2412	likely benign
SaProt	LLR -10.19	damaging
⇒ SaProt calls this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.9	GERP 2.5, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 7,830 bp · p 0.26 · regional, not allelic
Overall
CADD	23.5	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 2.18% African / African-American · 1,631/74,972 alleles

Filtering AF 2.09% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.05%

Overall 0.124% 1,996/1,612,246 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.18%	46
Admixed American	0.257%	389
Remaining individualsnot grpmax-eligible	0.221%	452
Middle Eastern	0.0496%	2,017
South Asian	0.00989%	10,109
European (non-Finnish)	0.00517%	19,329

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: ACTN3
Protein: p.Glu856Val
Coding: c.2567A>T
MANE Select: NM_001104
dbSNP: rs115296201
Type: single nucleotide variant
Location: chr11:66563054 (GRCh38)
Gene constraint: LOEUF 0.944 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.61 · 3 PDB
Residue 856: a UniProt-annotated variant site (very low expression, if any, at the protein level in skeletal muscle)

Full ACTN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ACTN3-related disorder

Similar variants

ACTN3 c.1129-8C>T Likely benign same condition
ACTN3 c.1678-8G>A Benign same condition
ACTN3 p.Ala417Ser Benign same condition
ACTN3 p.Ala469= Likely benign same condition
ACTN3 p.Ala492= Likely benign same condition
ACTN3 p.Ala564= Likely benign same condition
ACTN3 p.Ala881Ser Likely benign ⚠ same condition
ACTN3 p.Arg199Gln Likely benign 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/actn3-p-glu856val (accessed [today's date]).

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