Is ACTN2 p.Ser886Phe (c.2657C>T) pathogenic?

ACTN2 p.Ser886Phe (c.2657C>T) is classified Uncertain significance in ACTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-21). AlphaMissense: likely benign (0.2949); Absent from gnomAD v4.1; Associated with ACTN2-related disorder.

What condition is associated with ACTN2 p.Ser886Phe (c.2657C>T)?

ACTN2 p.Ser886Phe (c.2657C>T) is associated with ACTN2-related disorder (ClinVar).

How common is ACTN2 p.Ser886Phe (c.2657C>T) in the general population?

ACTN2 p.Ser886Phe (c.2657C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTN2 p.Ser886Phe (c.2657C>T)?

AlphaMissense predicts likely benign (score 0.2949) — an in-silico prediction, not a clinical call.

ACTN2 p.Ser886Phe

c.2657C>T · rs2527670346 · VCV2629621

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2949 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

ACTN2-related disorder

Computational evidence

Protein change
AlphaMissense	0.2949	likely benign
REVEL	0.293	indeterminate
SaProt	LLR -12.06	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.1, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 25 kb · p 0.0054 · 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACTN2
Protein: p.Ser886Phe
Coding: c.2657C>T
MANE Select: NM_001103
dbSNP: rs2527670346
Type: single nucleotide variant
Location: chr1:236762591 (GRCh38)
Gene constraint: LOEUF 0.432 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.88 · 18 PDB
Residue 886: an α-helix

Full ACTN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ACTN2-related disorder

Similar variants

ACTN2 p.Ser886Pro Uncertain significance ★★ ⚠ same residue
ACTN2 p.Ser886= Likely benign ★★ same residue
ACTN2 p.Ala119Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
ACTN2 p.Gly723Glu Uncertain significance ★★ ⚠ same condition
ACTN2 p.Ala410Ser Conflicting classifications of pathogenicity ★ ⚠ same condition
ACTN2 p.Pro598Gln Uncertain significance ★ ⚠ same condition
ACTN2 p.Tyr681His Uncertain significance ★ ⚠ same condition
ACTN2 p.Asn714Ile 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/actn2-p-ser886phe (accessed [today's date]).

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