Is ACTN1 p.Pro892His (c.2675C>A) pathogenic?

ACTN1 p.Pro892His (c.2675C>A) is classified Uncertain significance in ACTN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: likely benign (0.0851); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with ACTN1 p.Pro892His (c.2675C>A)?

ACTN1 p.Pro892His (c.2675C>A) is associated with Inborn genetic diseases (ClinVar).

How common is ACTN1 p.Pro892His (c.2675C>A) in the general population?

ACTN1 p.Pro892His (c.2675C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTN1 p.Pro892His (c.2675C>A)?

AlphaMissense predicts likely benign (score 0.0851) — an in-silico prediction, not a clinical call.

ACTN1 p.Pro892His

c.2675C>A · VCV4221715

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0851 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0851	likely benign
REVEL	0.25	benign-leaning
SaProt	LLR -9.10	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 2,221 bp · p 0.0072 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P870H vs ClinVar P892H) — verify the residue.

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.Pro892His
Coding: c.2675C>A
MANE Select: NM_001130004
Type: single nucleotide variant
Location: chr14:68874929 (GRCh38)
Gene constraint: LOEUF 0.331 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.39 · 4 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACTN1 p.Ala48Val Uncertain significance ★★ ⚠ same condition
ACTN1 p.Arg475His Uncertain significance ★★ ⚠ same condition
ACTN1 p.Asn824Ser Uncertain significance ★★ ⚠ same condition
ACTN1 p.Asp11Asn Uncertain significance ★★ ⚠ same condition
ACTN1 p.Asp868Asn Uncertain significance ★★ ⚠ same condition
ACTN1 p.Asp868Gly Uncertain significance ★★ ⚠ same condition
ACTN1 p.Glu273Lys Uncertain significance ★★ ⚠ same condition
ACTN1 p.Glu423Gly 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/actn1-p-pro892his (accessed [today's date]).

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