Is ACTA1 p.Ala116Pro (c.346G>C) pathogenic?

ACTA1 p.Ala116Pro (c.346G>C) is classified Likely pathogenic in ACTA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-01). AlphaMissense: likely pathogenic (0.7947); Absent from gnomAD v4.1; Associated with nemaline myopathy.

What condition is associated with ACTA1 p.Ala116Pro (c.346G>C)?

ACTA1 p.Ala116Pro (c.346G>C) is associated with nemaline myopathy (ClinVar).

How common is ACTA1 p.Ala116Pro (c.346G>C) in the general population?

ACTA1 p.Ala116Pro (c.346G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTA1 p.Ala116Pro (c.346G>C)?

AlphaMissense predicts likely pathogenic (score 0.7947) — an in-silico prediction, not a clinical call.

ACTA1 p.Ala116Pro

c.346G>C · rs1659975786 · VCV3233260

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7947 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nemaline myopathy

Computational evidence

Protein change
AlphaMissense	0.7947	likely pathogenic ✓ concordant with ClinVar
REVEL	0.936	strongly pathogenic-leaning
SaProt	LLR -11.64	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 7.6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.33	constrained · MANE · 1,613 bp · p 1.6e-54 · regional, not allelic
Overall
CADD	30.0	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

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: ACTA1
Protein: p.Ala116Pro
Coding: c.346G>C
MANE Select: NM_001100
dbSNP: rs1659975786
Type: single nucleotide variant
Location: chr1:229432664 (GRCh38)
Gene constraint: LOEUF 0.931 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.21 · 5 PDB
Residue 116: an α-helix; the 'interaction with alpha-actinin' region; a UniProt-annotated variant site (in cmyo2a)

Full ACTA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nemaline myopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACTA1 p.Ala116Thr Likely pathogenic ★★ ⚠ same residue
ACTA1 p.Ala116Val Likely pathogenic ★★ ⚠ same residue
ACTA1 p.Ala116Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
ACTA1 p.Glu59Lys Likely pathogenic ★★★ same condition
ACTA1 p.Gly148Val Likely pathogenic ★★★ same condition
ACTA1 p.Met229Thr Pathogenic ★★★ same condition
ACTA1 p.Glu255Gln Likely pathogenic ★★ same condition
ACTA1 p.Arg258Gly Likely pathogenic ★ 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/acta1-p-ala116pro (accessed [today's date]).

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