Is ACTL6B p.Ala176Val (c.527C>T) pathogenic?

ACTL6B p.Ala176Val (c.527C>T) is classified Uncertain significance in ACTL6B (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-08-23). AlphaMissense: likely pathogenic (0.9147); Absent from gnomAD v4.1; Associated with ACTL6B-related disorder.

What condition is associated with ACTL6B p.Ala176Val (c.527C>T)?

ACTL6B p.Ala176Val (c.527C>T) is associated with ACTL6B-related disorder (ClinVar).

How common is ACTL6B p.Ala176Val (c.527C>T) in the general population?

ACTL6B p.Ala176Val (c.527C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTL6B p.Ala176Val (c.527C>T)?

AlphaMissense predicts likely pathogenic (score 0.9147) — an in-silico prediction, not a clinical call.

ACTL6B p.Ala176Val

c.527C>T · VCV3346769

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9147 · 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	0.9147	likely pathogenic
REVEL	0.648	pathogenic-leaning
SaProt	LLR -9.59	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 5, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 9,273 bp · p 1.9e-09 · regional, not allelic
Overall
CADD	29.6	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.Ala176Val
Coding: c.527C>T
MANE Select: NM_016188
Type: single nucleotide variant
Location: chr7:100648764 (GRCh38)
Gene constraint: LOEUF 0.954 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.52
Residue 176: a UniProt-annotated variant site (in dee76)

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

Disease context

ACTL6B-related disorder

Similar variants

ACTL6B p.Gly343Arg Pathogenic/Likely pathogenic ★★ same condition
ACTL6B c.103-1G>C Likely pathogenic ★ same condition
ACTL6B p.Cys420Ter Likely pathogenic ★ same condition
ACTL6B c.562+5G>A Uncertain significance ★ same condition
ACTL6B p.Arg386Cys Uncertain significance ★ ⚠ same condition
ACTL6B p.Cys425Ter Conflicting classifications of pathogenicity ★ same condition
ACTL6B p.His180Tyr Uncertain significance ★ ⚠ same condition
ACTL6B c.669+1G>A 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-ala176val (accessed [today's date]).

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