Is ACTN1 p.Leu668Pro (c.2003T>C) pathogenic?

ACTN1 p.Leu668Pro (c.2003T>C) is classified Likely pathogenic in ACTN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-05-26). AlphaMissense: likely pathogenic (0.9961); Absent from gnomAD v4.1; Associated with platelet-type bleeding disorder 15.

What condition is associated with ACTN1 p.Leu668Pro (c.2003T>C)?

ACTN1 p.Leu668Pro (c.2003T>C) is associated with platelet-type bleeding disorder 15 (ClinVar).

How common is ACTN1 p.Leu668Pro (c.2003T>C) in the general population?

ACTN1 p.Leu668Pro (c.2003T>C) is absent from gnomAD v4.1 (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.Leu668Pro (c.2003T>C)?

AlphaMissense predicts likely pathogenic (score 0.9961) — an in-silico prediction, not a clinical call.

ACTN1 p.Leu668Pro

c.2003T>C · VCV4531487

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9961 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

platelet-type bleeding disorder 15

Computational evidence

Protein change
AlphaMissense	0.9961	likely pathogenic ✓ concordant with ClinVar
REVEL	0.828	moderately pathogenic-leaning
SaProt	LLR -18.09	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	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.Leu668Pro
Coding: c.2003T>C
MANE Select: NM_001130004
Type: single nucleotide variant
Location: chr14:68880940 (GRCh38)
Gene constraint: LOEUF 0.331 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.39 · 4 PDB
Residue 668: the 'interaction with ddn' 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.Leu668= Likely benign ★ 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-leu668pro (accessed [today's date]).

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