Is ACTL6A p.Pro219Ser (c.655C>T) pathogenic?

ACTL6A p.Pro219Ser (c.655C>T) is classified Uncertain significance in ACTL6A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-01). AlphaMissense: likely pathogenic (0.7253); Very rare (popmax 0.00017%, nfe).

How common is ACTL6A p.Pro219Ser (c.655C>T) in the general population?

ACTL6A p.Pro219Ser (c.655C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about ACTL6A p.Pro219Ser (c.655C>T)?

AlphaMissense predicts likely pathogenic (score 0.7253) — an in-silico prediction, not a clinical call.

ACTL6A p.Pro219Ser

c.655C>T · rs2474128006 · VCV2654291

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7253 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7253	likely pathogenic
REVEL	0.8	moderately pathogenic-leaning
SaProt	LLR -14.12	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 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 25 kb · p 5.7e-26 · regional, not allelic
Overall
CADD	27.1	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 0.00017% European (non-Finnish) · 2/1,179,380 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,102 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: ACTL6A
Protein: p.Pro219Ser
Coding: c.655C>T
MANE Select: NM_004301
dbSNP: rs2474128006
Type: single nucleotide variant
Location: chr3:179576703 (GRCh38)
Gene constraint: LOEUF 0.186 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 92.04 · 31 PDB

Full ACTL6A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACTL6A p.Arg389Trp Uncertain significance ★★ ⚠ same type
ACTL6A p.Arg390Ser Uncertain significance ★★ ⚠ same type
ACTL6A p.Asp339= Benign ★★ same type
ACTL6A c.1209+1G>C Uncertain significance ★ same type
ACTL6A c.477-1G>C Uncertain significance ★ same type
ACTL6A c.477-2A>G Uncertain significance ★ same type
ACTL6A c.572-4A>G Uncertain significance ★ same type
ACTL6A c.768+1G>A 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/actl6a-p-pro219ser (accessed [today's date]).

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