Is ACTL6B p.Arg227Trp (c.679C>T) pathogenic?

ACTL6B p.Arg227Trp (c.679C>T) is classified Uncertain significance in ACTL6B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-17). AlphaMissense: likely pathogenic (0.8655); Very rare (popmax 0.00268%, afr); Associated with Inborn genetic diseases.

What condition is associated with ACTL6B p.Arg227Trp (c.679C>T)?

ACTL6B p.Arg227Trp (c.679C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ACTL6B p.Arg227Trp (c.679C>T) in the general population?

ACTL6B p.Arg227Trp (c.679C>T) is very rare (popmax 0.00268%, afr) (gnomAD).

What do computational predictors say about ACTL6B p.Arg227Trp (c.679C>T)?

AlphaMissense predicts likely pathogenic (score 0.8655) — an in-silico prediction, not a clinical call.

ACTL6B p.Arg227Trp

c.679C>T · rs749531229 · VCV2598129

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8655 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00268%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8655	likely pathogenic
REVEL	0.94	strongly pathogenic-leaning
SaProt	LLR -10.85	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.22	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 7.5	GERP 2.8, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 9,273 bp · p 1.9e-09 · regional, not allelic
Overall
CADD	28.6	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

Grpmax group 0.00268% African / African-American · 2/74,640 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00109%

Overall 0.00169% 27/1,600,018 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00268%	37,320
East Asian	0.00223%	44,828
European (non-Finnish)	0.00196%	51,014
Remaining individualsnot grpmax-eligible	0.00161%	61,928

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: ACTL6B
Protein: p.Arg227Trp
Coding: c.679C>T
MANE Select: NM_016188
dbSNP: rs749531229
Type: single nucleotide variant
Location: chr7:100647524 (GRCh38)
Gene constraint: LOEUF 0.954 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.52
Residue 227: a UniProt-annotated variant site (in dee76)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACTL6B p.Arg227Gln Uncertain significance ★ ⚠ same residue
ACTL6B p.Ile408Thr Uncertain significance ★★ ⚠ same condition
ACTL6B p.Met201Ile Uncertain significance ★★ ⚠ same condition
ACTL6B p.Pro232Arg Uncertain significance ★★ ⚠ same condition
ACTL6B p.Ala156Thr Uncertain significance ★ ⚠ same condition
ACTL6B p.Ala379Thr Uncertain significance ★ ⚠ same condition
ACTL6B p.Arg24Leu Uncertain significance ★ ⚠ same condition
ACTL6B p.Arg423Gly 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-arg227trp (accessed [today's date]).

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