Is ACTL6B p.Pro371Leu (c.1112C>T) pathogenic?

ACTL6B p.Pro371Leu (c.1112C>T) is classified Likely pathogenic in ACTL6B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-08). AlphaMissense: likely pathogenic (0.5755); Ultra-rare (popmax 0.0165%, mid).

How common is ACTL6B p.Pro371Leu (c.1112C>T) in the general population?

ACTL6B p.Pro371Leu (c.1112C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ACTL6B p.Pro371Leu (c.1112C>T)?

AlphaMissense predicts likely pathogenic (score 0.5755) — an in-silico prediction, not a clinical call.

ACTL6B p.Pro371Leu

c.1112C>T · VCV4282457

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5755 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5755	likely pathogenic ✓ concordant with ClinVar
REVEL	0.796	moderately pathogenic-leaning
SaProt	LLR -9.88	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 4.9, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 3,523 bp · p 8.1e-06 · regional, not allelic
Overall
CADD	35.0	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

Grpmax group 0.0165% Middle Eastern · 1/6,050 alleles

Overall 6.84e-05% 1/1,461,732 alleles · ultra-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.Pro371Leu
Coding: c.1112C>T
MANE Select: NM_016188
Type: single nucleotide variant
Location: chr7:100646552 (GRCh38)
Gene constraint: LOEUF 0.954 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.52
Residue 371: a UniProt-annotated variant site (in dee76)

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

Similar variants

ACTL6B p.Pro371Ala Likely pathogenic ★ ⚠ same residue
ACTL6B p.Pro371Arg Pathogenic ★ same residue
ACTL6B p.Arg97Ter Likely pathogenic ★★ same type
ACTL6B p.Gln186Ter Pathogenic/Likely pathogenic ★★ same type
ACTL6B p.Gln278Ter Likely pathogenic ★★ same type
ACTL6B p.Gly343Arg Pathogenic/Likely pathogenic ★★ same type
ACTL6B p.Gly349Ser Likely pathogenic ★★ same type
ACTL6B p.Trp247Ter Likely pathogenic ★★ same type

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-pro371leu (accessed [today's date]).

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