Is ACTN1 p.Arg714Pro (c.2141G>C) pathogenic?

ACTN1 p.Arg714Pro (c.2141G>C) is classified Uncertain significance in ACTN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-14). AlphaMissense: likely pathogenic (0.9989); Absent from gnomAD v4.1.

How common is ACTN1 p.Arg714Pro (c.2141G>C) in the general population?

ACTN1 p.Arg714Pro (c.2141G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTN1 p.Arg714Pro (c.2141G>C)?

AlphaMissense predicts likely pathogenic (score 0.9989) — an in-silico prediction, not a clinical call.

ACTN1 p.Arg714Pro

c.2141G>C · rs1383792017 · VCV2837607

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9989 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9989	likely pathogenic · top 7% in ACTN1
REVEL	0.778	moderately pathogenic-leaning
SaProt	LLR -15.19	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	34.0	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

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: ACTN1
Protein: p.Arg714Pro
Coding: c.2141G>C
MANE Select: NM_001130004
dbSNP: rs1383792017
Type: single nucleotide variant
Location: chr14:68880101 (GRCh38)
Gene constraint: LOEUF 0.331 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.39 · 4 PDB
Residue 714: the 'interaction with ddn' region

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

Similar variants

ACTN1 p.Arg714Cys Uncertain significance ★★ ⚠ same residue
ACTN1 p.Arg714Gly Uncertain significance ★ ⚠ same residue
ACTN1 p.Arg714His Conflicting classifications of pathogenicity ★ ⚠ same residue
ACTN1 p.Arg714Ser Uncertain significance ★ ⚠ same residue
ACTN1 p.Arg714= Likely benign ★ same residue
ACTN1 p.Arg450Cys Pathogenic/Likely pathogenic ★★ same type
ACTN1 p.Arg46Gln Pathogenic/Likely pathogenic ★★ same type
ACTN1 p.Arg46Trp Pathogenic/Likely pathogenic ★★ 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/actn1-p-arg714pro (accessed [today's date]).

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