Is ACTR8 p.Pro68Ala (c.202C>G) pathogenic?

ACTR8 p.Pro68Ala (c.202C>G) is classified Uncertain significance in ACTR8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-23). AlphaMissense: likely pathogenic (0.6994); Very rare (popmax 0.00223%, eas).

How common is ACTR8 p.Pro68Ala (c.202C>G) in the general population?

ACTR8 p.Pro68Ala (c.202C>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ACTR8 p.Pro68Ala (c.202C>G)?

AlphaMissense predicts likely pathogenic (score 0.6994) — an in-silico prediction, not a clinical call.

ACTR8 p.Pro68Ala

c.202C>G · rs772847580 · VCV3142672

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6994 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6994	likely pathogenic
REVEL	0.795	moderately pathogenic-leaning
SaProt	LLR -10.29	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 2.4, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 13 kb · p 0.0002 · regional, not allelic
Overall
CADD	27.6	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 0.00223% East Asian · 1/44,898 alleles

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

Overall 0.000186% 3/1,614,068 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,898
European (non-Finnish)	0.000169%	590,012

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: ACTR8
Protein: p.Pro68Ala
Coding: c.202C>G
MANE Select: NM_022899
dbSNP: rs772847580
Type: single nucleotide variant
Location: chr3:53880031 (GRCh38)
Gene constraint: LOEUF 1.033 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.30 · 1 PDB

Full ACTR8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACTR8 c.406-7T>G Benign ★★ same type
ACTR8 p.Ala171Ser Uncertain significance ★ ⚠ same type
ACTR8 p.Ala270Thr Uncertain significance ★ ⚠ same type
ACTR8 p.Ala388Ser Uncertain significance ★ ⚠ same type
ACTR8 p.Ala427Ser Uncertain significance ★ ⚠ same type
ACTR8 p.Ala436Glu Uncertain significance ★ ⚠ same type
ACTR8 p.Ala483Val Uncertain significance ★ ⚠ same type
ACTR8 p.Ala585Pro 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/actr8-p-pro68ala (accessed [today's date]).

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