Is ACTL6B p.Pro38Ser (c.112C>T) pathogenic?

ACTL6B p.Pro38Ser (c.112C>T) is classified Uncertain significance in ACTL6B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-14). AlphaMissense: likely pathogenic (0.9095); Very rare (popmax 0.000509%, nfe).

How common is ACTL6B p.Pro38Ser (c.112C>T) in the general population?

ACTL6B p.Pro38Ser (c.112C>T) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about ACTL6B p.Pro38Ser (c.112C>T)?

AlphaMissense predicts likely pathogenic (score 0.9095) — an in-silico prediction, not a clinical call.

ACTL6B p.Pro38Ser

c.112C>T · VCV4525947

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9095 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9095	likely pathogenic
REVEL	0.872	moderately pathogenic-leaning
SaProt	LLR -10.26	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 3.7, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 9,273 bp · p 1.9e-09 · regional, not allelic
Overall
CADD	28.1	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 0.000509% European (non-Finnish) · 6/1,179,330 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000411% 6/1,460,418 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.Pro38Ser
Coding: c.112C>T
MANE Select: NM_016188
Type: single nucleotide variant
Location: chr7:100655577 (GRCh38)
Gene constraint: LOEUF 0.954 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.52

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

Similar variants

ACTL6B p.Pro38Ala Uncertain significance ★ ⚠ 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
ACTL6B p.Arg363Gln Uncertain significance ★★ ⚠ 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-pro38ser (accessed [today's date]).

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