Is ACTL6B p.Gly343Trp (c.1027G>T) pathogenic?

ACTL6B p.Gly343Trp (c.1027G>T) is classified Likely pathogenic in ACTL6B (ClinVar, Single submitter, 2 submitters; last evaluated 2022-09-01). AlphaMissense: likely pathogenic (0.9775); Absent from gnomAD v4.1; Associated with intellectual developmental disorder with severe speech and ambulation defects.

What condition is associated with ACTL6B p.Gly343Trp (c.1027G>T)?

ACTL6B p.Gly343Trp (c.1027G>T) is associated with intellectual developmental disorder with severe speech and ambulation defects (ClinVar).

How common is ACTL6B p.Gly343Trp (c.1027G>T) in the general population?

ACTL6B p.Gly343Trp (c.1027G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTL6B p.Gly343Trp (c.1027G>T)?

AlphaMissense predicts likely pathogenic (score 0.9775) — an in-silico prediction, not a clinical call.

ACTL6B p.Gly343Trp

c.1027G>T · rs1131692228 · VCV1705593

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9775 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual developmental disorder with severe speech and ambulation defects

Computational evidence

Protein change
AlphaMissense	0.9775	likely pathogenic ✓ concordant with ClinVar
REVEL	0.812	moderately pathogenic-leaning
SaProt	LLR -14.05	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.37 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 4.9, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 3,523 bp · p 8.1e-06 · regional, not allelic
Overall
CADD	28.7	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

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: ACTL6B
Protein: p.Gly343Trp
Coding: c.1027G>T
MANE Select: NM_016188
dbSNP: rs1131692228
Type: single nucleotide variant
Location: chr7:100646637 (GRCh38)
Gene constraint: LOEUF 0.954 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.52
Residue 343: a UniProt-annotated variant site (in dee76); a UniProt-annotated variant site (in iddssad; probable gain-of-function mutation)

Full ACTL6B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual developmental disorder with severe speech and ambulation defects — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACTL6B p.Gly343Arg Pathogenic/Likely pathogenic ★★ same residue
ACTL6B p.Arg97Ter Likely pathogenic ★★ same condition
ACTL6B p.Arg363Gln Uncertain significance ★★ ⚠ same condition
ACTL6B p.Val421Met Uncertain significance ★★ ⚠ same condition
ACTL6B c.*98T>A Benign ★★ same condition
ACTL6B p.Asn125Lys Likely pathogenic ★ same condition
ACTL6B p.Leu185Pro Likely pathogenic ★ same condition
ACTL6B p.Ala46Thr 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/actl6b-p-gly343trp (accessed [today's date]).

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