Is ACTL6B p.Ser22Pro (c.64T>C) pathogenic?

ACTL6B p.Ser22Pro (c.64T>C) is classified Uncertain significance in ACTL6B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely pathogenic (0.9946); Absent from gnomAD v4.1.

How common is ACTL6B p.Ser22Pro (c.64T>C) in the general population?

ACTL6B p.Ser22Pro (c.64T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTL6B p.Ser22Pro (c.64T>C)?

AlphaMissense predicts likely pathogenic (score 0.9946) — an in-silico prediction, not a clinical call.

ACTL6B p.Ser22Pro

c.64T>C · VCV3366029

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9946 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,576,266)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9946	likely pathogenic
REVEL	0.881	moderately pathogenic-leaning
SaProt	LLR -13.47	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 9.2	GERP -0.95, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 9,273 bp · p 1.9e-09 · regional, not allelic
Overall
CADD	29.0	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

No allele count reported in gnomAD v4.1 (AN 1,576,266). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: ACTL6B
Protein: p.Ser22Pro
Coding: c.64T>C
MANE Select: NM_016188
Type: single nucleotide variant
Location: chr7:100655841 (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.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
ACTL6B p.Glu297Lys 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-ser22pro (accessed [today's date]).

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