Is ACTN1 p.Arg76His (c.227G>A) pathogenic?

ACTN1 p.Arg76His (c.227G>A) is classified Likely benign in ACTN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-19). AlphaMissense: likely benign (0.2014); Very rare (popmax 0.00167%, amr).

How common is ACTN1 p.Arg76His (c.227G>A) in the general population?

ACTN1 p.Arg76His (c.227G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about ACTN1 p.Arg76His (c.227G>A)?

AlphaMissense predicts likely benign (score 0.2014) — an in-silico prediction, not a clinical call.

ACTN1 p.Arg76His

c.227G>A · VCV4750005

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2014 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2014	likely benign
REVEL	0.712	pathogenic-leaning
SaProt	LLR -14.06	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 16 kb · p 1.1e-15 · regional, not allelic
Overall
CADD	28.4	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 0.00167% Admixed American · 1/59,978 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00836% 135/1,613,946 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.201%	496
Admixed Americangrpmax	0.00167%	59,978
Remaining individualsnot grpmax-eligible	0.0016%	62,474
European (non-Finnish)	0.000339%	294,995

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ACTN1
Protein: p.Arg76His
Coding: c.227G>A
MANE Select: NM_001130004
Type: single nucleotide variant
Location: chr14:68921119 (GRCh38)
Gene constraint: LOEUF 0.331 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.39 · 4 PDB
Residue 76: the calponin-homology (ch) 1 domain; an α-helix; the 'actin-binding' region

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

Similar variants

ACTN1 p.Arg450Cys Pathogenic/Likely pathogenic ★★ same type
ACTN1 p.Arg46Gln Pathogenic/Likely pathogenic ★★ same type
ACTN1 p.Arg46Trp Pathogenic/Likely pathogenic ★★ same type
ACTN1 p.Glu225Lys Pathogenic ★★ same type
ACTN1 p.Leu547Pro Likely pathogenic ★★ ⚠ same type
ACTN1 p.Val105Ile Pathogenic/Likely pathogenic ★★ same type
ACTN1 p.Ala255Val Uncertain significance ★★ ⚠ same type
ACTN1 p.Ala48Val 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/actn1-p-arg76his (accessed [today's date]).

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