Is ACTL6B p.Pro241Thr (c.721C>A) pathogenic?

ACTL6B p.Pro241Thr (c.721C>A) is classified Uncertain significance in ACTL6B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-01). AlphaMissense: likely pathogenic (0.6624); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ACTL6B p.Pro241Thr (c.721C>A)?

ACTL6B p.Pro241Thr (c.721C>A) is associated with Inborn genetic diseases (ClinVar).

How common is ACTL6B p.Pro241Thr (c.721C>A) in the general population?

ACTL6B p.Pro241Thr (c.721C>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ACTL6B p.Pro241Thr (c.721C>A)?

AlphaMissense predicts likely pathogenic (score 0.6624) — an in-silico prediction, not a clinical call.

ACTL6B p.Pro241Thr

c.721C>A · rs2486159085 · VCV3141385

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6624 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6624	likely pathogenic
REVEL	0.782	moderately pathogenic-leaning
SaProt	LLR -11.60	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
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	29.3	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 8.48e-05% European (non-Finnish) · 1/1,178,940 alleles

Overall 6.85e-05% 1/1,459,676 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: ACTL6B
Protein: p.Pro241Thr
Coding: c.721C>A
MANE Select: NM_016188
dbSNP: rs2486159085
Type: single nucleotide variant
Location: chr7:100647482 (GRCh38)
Gene constraint: LOEUF 0.954 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.52
Residue 241: 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.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.Arg227Gln Uncertain significance ★ ⚠ same condition
ACTL6B p.Arg227Trp Uncertain significance ★ ⚠ same condition
ACTL6B p.Arg24Leu 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-pro241thr (accessed [today's date]).

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