Is ACVR1 p.Arg490Pro (c.1469G>C) pathogenic?

ACVR1 p.Arg490Pro (c.1469G>C) is classified Uncertain significance in ACVR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-30). AlphaMissense: likely pathogenic (0.999); Very rare (popmax 0.0011%, sas).

How common is ACVR1 p.Arg490Pro (c.1469G>C) in the general population?

ACVR1 p.Arg490Pro (c.1469G>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about ACVR1 p.Arg490Pro (c.1469G>C)?

AlphaMissense predicts likely pathogenic (score 0.999) — an in-silico prediction, not a clinical call.

ACVR1 p.Arg490Pro

c.1469G>C · VCV4716317

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.999 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.999	likely pathogenic · top 6% in ACVR1
REVEL	0.914	moderately pathogenic-leaning
SaProt	LLR -17.43	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 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 24 kb · p 0.003 · regional, not allelic
Overall
CADD	32.0	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

Grpmax group 0.0011% South Asian · 1/91,070 alleles

Overall 6.84e-05% 1/1,461,746 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: ACVR1
Protein: p.Arg490Pro
Coding: c.1469G>C
MANE Select: NM_001111067
Type: single nucleotide variant
Location: chr2:157737592 (GRCh38)
Gene constraint: LOEUF 0.835 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.70 · 85 PDB
Residue 490: the protein kinase domain; an α-helix

Full ACVR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACVR1 p.Arg490His Uncertain significance ★ ⚠ same residue
ACVR1 p.Arg490Cys Likely benign ★ same residue
ACVR1 p.Arg206His Pathogenic ★★ same type
ACVR1 p.Gly328Glu Pathogenic/Likely pathogenic ★★ same type
ACVR1 p.Gly356Asp Pathogenic/Likely pathogenic ★★ same type
ACVR1 p.Ala134Thr Uncertain significance ★★ ⚠ same type
ACVR1 p.Arg147Gln Uncertain significance ★★ ⚠ same type
ACVR1 p.Arg160Ter 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/acvr1-p-arg490pro (accessed [today's date]).

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