Is ACTN2 p.Arg327Pro (c.980G>C) pathogenic?

ACTN2 p.Arg327Pro (c.980G>C) is classified Uncertain significance in ACTN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-07-12). AlphaMissense: likely pathogenic (0.9964); Very rare (popmax 8.47e-05%, nfe).

How common is ACTN2 p.Arg327Pro (c.980G>C) in the general population?

ACTN2 p.Arg327Pro (c.980G>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ACTN2 p.Arg327Pro (c.980G>C)?

AlphaMissense predicts likely pathogenic (score 0.9964) — an in-silico prediction, not a clinical call.

ACTN2 p.Arg327Pro

c.980G>C · rs554811924 · VCV2690835

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9964 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9964	likely pathogenic · top 7% in ACTN2
REVEL	0.696	pathogenic-leaning
SaProt	LLR -15.61	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 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 25 kb · p 0.0054 · regional, not allelic
Overall
CADD	32.0	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,004 alleles

Overall 0.000658% 1/151,996 alleles · very rare

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: ACTN2
Protein: p.Arg327Pro
Coding: c.980G>C
MANE Select: NM_001103
dbSNP: rs554811924
Type: single nucleotide variant
Location: chr1:236739405 (GRCh38)
Gene constraint: LOEUF 0.432 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.88 · 18 PDB
Residue 327: an α-helix

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

Similar variants

ACTN2 p.Arg327Cys Uncertain significance ★★ ⚠ same residue
ACTN2 p.Arg327His Conflicting classifications of pathogenicity ★ ⚠ same residue
ACTN2 p.Ala119Thr Pathogenic/Likely pathogenic ★★ same type
ACTN2 p.Leu727Arg Pathogenic/Likely pathogenic ★★ same type
ACTN2 p.Thr247Met Likely pathogenic ★★ same type
ACTN2 c.1107+3G>A Uncertain significance ★★ same type
ACTN2 c.1108-10A>G Uncertain significance ★★ same type
ACTN2 c.1255+1G>C Uncertain significance ★★ 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/actn2-p-arg327pro (accessed [today's date]).

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