Is ACTB p.Met44Ile (c.132G>A) pathogenic?

ACTB p.Met44Ile (c.132G>A) is classified Uncertain significance in ACTB (ClinVar, Single submitter, 2 submitters; last evaluated 2025-11-19). AlphaMissense: likely pathogenic (0.9968); Absent from gnomAD v4.1; Associated with ACTB-associated syndromic thrombocytopenia.

What condition is associated with ACTB p.Met44Ile (c.132G>A)?

ACTB p.Met44Ile (c.132G>A) is associated with ACTB-associated syndromic thrombocytopenia (ClinVar).

How common is ACTB p.Met44Ile (c.132G>A) in the general population?

ACTB p.Met44Ile (c.132G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTB p.Met44Ile (c.132G>A)?

AlphaMissense predicts likely pathogenic (score 0.9968) — an in-silico prediction, not a clinical call.

ACTB p.Met44Ile

Q: How is Actinomyopathy-associated syndromic thrombocytopenia inherited?

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

c.132G>A · VCV3344344

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9968 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,614,036)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

ACTB-associated syndromic thrombocytopenia

Computational evidence

Protein change
AlphaMissense	0.9968	likely pathogenic
REVEL	0.6	indeterminate
SaProt	LLR -11.35	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 4.8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.12	constrained · MANE · 289 bp · p 4.5e-15 · regional, not allelic
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,614,036). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: ACTB
Protein: p.Met44Ile
Coding: c.132G>A
MANE Select: NM_001101
Type: single nucleotide variant
Location: chr7:5529392 (GRCh38)
Gene constraint: LOEUF 0.193 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 95.31 · 93 PDB
Residue 44: a β-strand; a modified residue (methionine (r)-sulfoxide)

Full ACTB gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ACTB-associated syndromic thrombocytopenia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Actinomyopathy-associated syndromic thrombocytopenia (Orphanet):

Inheritance: Autosomal dominant

Similar variants

ACTB p.Ala22Thr Likely pathogenic ★★ same condition
ACTB p.Leu171Phe Pathogenic/Likely pathogenic ★★ same condition
ACTB p.Arg312Ser Likely pathogenic ★ same condition
ACTB p.Trp356Ter Likely pathogenic ★ same condition
ACTB p.Glu195Gln Uncertain significance ★ ⚠ same condition
ACTB p.Met283Thr Uncertain significance ★ ⚠ same condition
ACTB p.Glu364Lys Conflicting classifications of pathogenicity ⚠ same condition
ACTB p.Ala331fs 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/actb-p-met44ile (accessed [today's date]).

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