Is ACTN1 p.Ile595Ser (c.1784T>G) pathogenic?

ACTN1 p.Ile595Ser (c.1784T>G) is classified Uncertain significance in ACTN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-04). AlphaMissense: likely pathogenic (0.8822); Absent from gnomAD v4.1.

How common is ACTN1 p.Ile595Ser (c.1784T>G) in the general population?

ACTN1 p.Ile595Ser (c.1784T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTN1 p.Ile595Ser (c.1784T>G)?

AlphaMissense predicts likely pathogenic (score 0.8822) — an in-silico prediction, not a clinical call.

ACTN1 p.Ile595Ser

c.1784T>G · rs2503226373 · VCV2877737

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8822 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8822	likely pathogenic
REVEL	0.567	indeterminate
SaProt	LLR -9.77	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 32 kb · p 3.7e-34 · regional, not allelic
Overall
CADD	31.0	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: ACTN1
Protein: p.Ile595Ser
Coding: c.1784T>G
MANE Select: NM_001130004
dbSNP: rs2503226373
Type: single nucleotide variant
Location: chr14:68882907 (GRCh38)
Gene constraint: LOEUF 0.331 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.39 · 4 PDB
Residue 595: the 'interaction with ddn' 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-ile595ser (accessed [today's date]).

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