Is ACTN1 p.Ser43Ala (c.127T>G) pathogenic?

ACTN1 p.Ser43Ala (c.127T>G) is classified Conflicting classifications of pathogenicity in ACTN1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-06-27). AlphaMissense: likely pathogenic (0.5816); Ultra-rare (popmax 0.033%, mid); Associated with platelet-type bleeding disorder 15.

What condition is associated with ACTN1 p.Ser43Ala (c.127T>G)?

ACTN1 p.Ser43Ala (c.127T>G) is associated with platelet-type bleeding disorder 15 (ClinVar).

How common is ACTN1 p.Ser43Ala (c.127T>G) in the general population?

ACTN1 p.Ser43Ala (c.127T>G) is ultra-rare (popmax 0.033%, mid) (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.Ser43Ala (c.127T>G)?

AlphaMissense predicts likely pathogenic (score 0.5816) — an in-silico prediction, not a clinical call.

ACTN1 p.Ser43Ala

c.127T>G · rs769375482 · VCV1957245

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.5816 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

platelet-type bleeding disorder 15

Computational evidence

Protein change
AlphaMissense	0.5816	likely pathogenic
REVEL	0.832	moderately pathogenic-leaning
SaProt	LLR -11.12	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 53 kb · p 0.074 · regional, not allelic
Overall
CADD	29.4	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 0.033% Middle Eastern · 2/6,056 alleles

Filtering AF 0.0163% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0138%

Overall 0.00161% 26/1,612,866 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,028
South Asian	0.0242%	4,130
Remaining individualsnot grpmax-eligible	0.0032%	31,228

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.Ser43Ala
Coding: c.127T>G
MANE Select: NM_001130004
dbSNP: rs769375482
Type: single nucleotide variant
Location: chr14:68925651 (GRCh38)
Gene constraint: LOEUF 0.331 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.39 · 4 PDB
Residue 43: 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.Ser43Thr Likely pathogenic same residue
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

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-ser43ala (accessed [today's date]).

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