Is ACTB p.Asp222Glu (c.666C>G) pathogenic?

ACTB p.Asp222Glu (c.666C>G) is classified Uncertain significance in ACTB (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-12-18). AlphaMissense: likely pathogenic (0.8214); Absent from gnomAD v4.1; Associated with ACTB-related disorder.

What condition is associated with ACTB p.Asp222Glu (c.666C>G)?

ACTB p.Asp222Glu (c.666C>G) is associated with ACTB-related disorder (ClinVar).

How common is ACTB p.Asp222Glu (c.666C>G) in the general population?

ACTB p.Asp222Glu (c.666C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTB p.Asp222Glu (c.666C>G)?

AlphaMissense predicts likely pathogenic (score 0.8214) — an in-silico prediction, not a clinical call.

ACTB p.Asp222Glu

c.666C>G · rs542398772 · VCV3061510

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8214 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ACTB-related disorder

Computational evidence

Protein change
AlphaMissense	0.8214	likely pathogenic
REVEL	0.878	moderately pathogenic-leaning
SaProt	LLR -13.33	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 5.6	GERP 0.77, phastCons 1
Regional constraint	o/e 0.11	constrained · MANE · 1,149 bp · p 1.6e-51 · regional, not allelic
Overall
CADD	25.5	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

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: ACTB
Protein: p.Asp222Glu
Coding: c.666C>G
MANE Select: NM_001101
dbSNP: rs542398772
Type: single nucleotide variant
Location: chr7:5528417 (GRCh38)
Gene constraint: LOEUF 0.193 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 95.31 · 93 PDB

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

Disease context

ACTB-related disorder

Similar variants

ACTB p.Asp222Ala Uncertain significance ★ same residue
ACTB p.Arg183Trp Pathogenic ★★ same condition
ACTB p.Arg206Gly Likely pathogenic ★★ same condition
ACTB p.His40Tyr Pathogenic/Likely pathogenic ★★ same condition
ACTB p.Val159Ala Likely pathogenic ★★ same condition
ACTB p.Val209Leu Likely pathogenic ★★ same condition
ACTB p.Val209Met Pathogenic/Likely pathogenic ★★ same condition
ACTB p.His101Tyr 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/actb-p-asp222glu (accessed [today's date]).

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