Is ACTN1 p.Ile130Val (c.388A>G) pathogenic?

ACTN1 p.Ile130Val (c.388A>G) is classified Likely pathogenic in ACTN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-19). AlphaMissense: ambiguous (0.4435); Very rare (popmax 0.00223%, eas); Associated with platelet-type bleeding disorder 15.

What condition is associated with ACTN1 p.Ile130Val (c.388A>G)?

ACTN1 p.Ile130Val (c.388A>G) is associated with platelet-type bleeding disorder 15 (ClinVar).

How common is ACTN1 p.Ile130Val (c.388A>G) in the general population?

ACTN1 p.Ile130Val (c.388A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Autosomal dominant macrothrombocytopenia inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ACTN1 p.Ile130Val (c.388A>G)?

AlphaMissense predicts ambiguous (score 0.4435) — an in-silico prediction, not a clinical call.

ACTN1 p.Ile130Val

c.388A>G · VCV3393125

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4435 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

platelet-type bleeding disorder 15

Computational evidence

Protein change
AlphaMissense	0.4435	ambiguous
REVEL	0.638	indeterminate
SaProt	LLR -6.88	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 16 kb · p 1.1e-15 · regional, not allelic
Overall
CADD	27.2	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 0.00223% East Asian · 1/44,880 alleles

Overall 0.000657% 1/152,122 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: ACTN1
Protein: p.Ile130Val
Coding: c.388A>G
MANE Select: NM_001130004
Type: single nucleotide variant
Location: chr14:68912195 (GRCh38)
Gene constraint: LOEUF 0.331 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.39 · 4 PDB
Residue 130: 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

Disease context

platelet-type bleeding disorder 15 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant macrothrombocytopenia (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood, Elderly, Infancy

Similar variants

ACTN1 p.Arg450Cys Pathogenic/Likely pathogenic ★★ same condition
ACTN1 p.Arg46Gln Pathogenic/Likely pathogenic ★★ same condition
ACTN1 p.Arg46Trp Pathogenic/Likely pathogenic ★★ same condition
ACTN1 p.Glu225Lys Pathogenic ★★ same condition
ACTN1 p.Leu547Pro Likely pathogenic ★★ ⚠ same condition
ACTN1 p.Val105Ile Pathogenic/Likely pathogenic ★★ same condition
ACTN1 p.Arg291Cys Uncertain significance ★★ ⚠ same condition
ACTN1 p.Arg825His 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-ile130val (accessed [today's date]).

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