Is ACTN1 p.Arg738Trp (c.2212C>T) pathogenic?

ACTN1 p.Arg738Trp (c.2212C>T) is classified Conflicting classifications of pathogenicity in ACTN1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-05-14). AlphaMissense: likely pathogenic (0.9937); Very rare (popmax 8.47e-05%, nfe); Associated with platelet-type bleeding disorder 15.

What condition is associated with ACTN1 p.Arg738Trp (c.2212C>T)?

ACTN1 p.Arg738Trp (c.2212C>T) is associated with platelet-type bleeding disorder 15 (ClinVar).

How common is ACTN1 p.Arg738Trp (c.2212C>T) in the general population?

ACTN1 p.Arg738Trp (c.2212C>T) is very rare (popmax 8.47e-05%, nfe) (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.Arg738Trp (c.2212C>T)?

AlphaMissense predicts likely pathogenic (score 0.9937) — an in-silico prediction, not a clinical call.

ACTN1 p.Arg738Trp

c.2212C>T · rs387907349 · VCV42032

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9937 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

platelet-type bleeding disorder 15

Computational evidence

Protein change
AlphaMissense	0.9937	likely pathogenic
REVEL	0.556	indeterminate
SaProt	LLR -19.46	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.3	phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 32 kb · p 3.7e-34 · regional, not allelic
Overall
CADD	32.0	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,012 alleles

Overall 6.84e-05% 1/1,461,850 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.Arg738Trp
Coding: c.2212C>T
MANE Select: NM_001130004
dbSNP: rs387907349
Type: single nucleotide variant
Location: chr14:68880030 (GRCh38)
Gene constraint: LOEUF 0.331 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.39 · 4 PDB
Residue 738: a UniProt-annotated variant site (in bdplt15)

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.Arg738Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
ACTN1 p.Arg738Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
ACTN1 p.Arg738Leu Uncertain significance ★ ⚠ 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

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-arg738trp (accessed [today's date]).

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