Is ACVRL1 p.Pro63= (c.189C>G) pathogenic?

ACVRL1 p.Pro63= (c.189C>G) is classified Likely benign in ACVRL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-24). Very rare (popmax 0.000428%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with ACVRL1 p.Pro63= (c.189C>G)?

ACVRL1 p.Pro63= (c.189C>G) is associated with Cardiovascular phenotype (ClinVar).

How common is ACVRL1 p.Pro63= (c.189C>G) in the general population?

ACVRL1 p.Pro63= (c.189C>G) is very rare (popmax 0.000428%, nfe) (gnomAD).

ACVRL1 p.Pro63=

c.189C>G · VCV4003224

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000428%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.34	GERP 1.2
Overall
CADD	2.195	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000428% European (non-Finnish) · 5/1,168,568 alleles

Filtering AF 0.000125% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.000315% 5/1,589,694 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: ACVRL1
Protein: p.Pro63=
Coding: c.189C>G
MANE Select: NM_000020
Type: single nucleotide variant
Location: chr12:51913226 (GRCh38)
Gene constraint: LOEUF 0.57 · pLI 0.51 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 82.77 · 7 PDB
Residue 63: a disulfide bond

Full ACVRL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACVRL1 c.1048+1G>A Pathogenic/Likely pathogenic ★★ same condition
ACVRL1 c.1049-1G>A Likely pathogenic ★★ same condition
ACVRL1 c.1246+1G>A Pathogenic ★★ same condition
ACVRL1 c.1246+2T>C Pathogenic ★★ same condition
ACVRL1 c.1378-1G>A Pathogenic ★★ same condition
ACVRL1 c.525+1G>A Pathogenic ★★ same condition
ACVRL1 c.525+2T>C Pathogenic ★★ same condition
ACVRL1 c.526-1G>A Pathogenic/Likely pathogenic ★★ same condition

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/acvrl1-p-pro63 (accessed [today's date]).

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