Is ACTB p.Val219Ile (c.655G>A) pathogenic?

ACTB p.Val219Ile (c.655G>A) is classified Likely pathogenic in ACTB (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-16). AlphaMissense: likely benign (0.2361); Very rare (popmax 6.84e-05%); Associated with neurodevelopmental disorder.

What condition is associated with ACTB p.Val219Ile (c.655G>A)?

ACTB p.Val219Ile (c.655G>A) is associated with neurodevelopmental disorder (ClinVar).

How common is ACTB p.Val219Ile (c.655G>A) in the general population?

ACTB p.Val219Ile (c.655G>A) is very rare (popmax 6.84e-05%) (gnomAD).

What do computational predictors say about ACTB p.Val219Ile (c.655G>A)?

AlphaMissense predicts likely benign (score 0.2361) — an in-silico prediction, not a clinical call.

ACTB p.Val219Ile

c.655G>A · VCV3376709

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2361 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

neurodevelopmental disorder

Computational evidence

Protein change
AlphaMissense	0.2361	likely benign ⚠ discordant with ClinVar
REVEL	0.531	indeterminate
SaProt	LLR -9.59	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.11	constrained · MANE · 1,149 bp · p 1.6e-51 · regional, not allelic
Overall
CADD	24.7	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 6.84e-05%

Overall 6.84e-05% 1/1,461,760 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: ACTB
Protein: p.Val219Ile
Coding: c.655G>A
MANE Select: NM_001101
Type: single nucleotide variant
Location: chr7:5528428 (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

neurodevelopmental disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACTB p.Val219= Likely benign ★★ same residue
ACTB p.Val219Leu Uncertain significance ★ ⚠ same residue
ACTB p.Asp56Tyr Likely pathogenic ★ same condition
ACTB p.Asp11del Likely pathogenic ★ same condition
ACTB p.Gln360fs Likely pathogenic ★ same condition
ACTB p.Lys118del Uncertain significance ★ same condition
ACTB p.Ala22Thr Likely pathogenic ★★ same type
ACTB p.Ala7Thr Likely pathogenic ★★ same type

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-val219ile (accessed [today's date]).

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