Is ACTL6B p.Gly343Arg (c.1027G>A) pathogenic?

ACTL6B p.Gly343Arg (c.1027G>A) is classified Pathogenic/Likely pathogenic in ACTL6B (ClinVar, Multiple submitters, 18 submitters; last evaluated 2026-06-29). AlphaMissense: likely pathogenic (0.9934); Absent from gnomAD v4.1; Associated with ACTL6B-related disorder.

What condition is associated with ACTL6B p.Gly343Arg (c.1027G>A)?

ACTL6B p.Gly343Arg (c.1027G>A) is associated with ACTL6B-related disorder, intellectual disability, autism (ClinVar).

How common is ACTL6B p.Gly343Arg (c.1027G>A) in the general population?

ACTL6B p.Gly343Arg (c.1027G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTL6B p.Gly343Arg (c.1027G>A)?

AlphaMissense predicts likely pathogenic (score 0.9934) — an in-silico prediction, not a clinical call.

ACTL6B p.Gly343Arg

c.1027G>A · rs1131692228 · VCV430804

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 18 submitters

AlphaMissense

likely pathogenic

0.9934 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ACTL6B-related disorder

Computational evidence

Protein change
AlphaMissense	0.9934	likely pathogenic ✓ concordant with ClinVar
REVEL	0.761	pathogenic-leaning
SaProt	LLR -8.58	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	Δ0.37	acceptor gain · deltas
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	33.0	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: ACTL6B
Protein: p.Gly343Arg
Coding: c.1027G>A
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

ACTL6B-related disorder

Also linked: intellectual disability autism intellectual developmental disorder with severe speech and ambulation defects

Similar variants

ACTL6B p.Gly343Trp 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 c.103-1G>C Likely pathogenic ★ same condition
ACTL6B p.Arg298Gln Likely pathogenic ★ same condition
ACTL6B p.Asn125Lys Likely 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/actl6b-p-gly343arg (accessed [today's date]).

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