Is ACVR1 p.Pro9Leu (c.26C>T) pathogenic?

ACVR1 p.Pro9Leu (c.26C>T) is classified Uncertain significance in ACVR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-15). AlphaMissense: likely benign (0.2141); Absent from gnomAD v4.1.

How common is ACVR1 p.Pro9Leu (c.26C>T) in the general population?

ACVR1 p.Pro9Leu (c.26C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACVR1 p.Pro9Leu (c.26C>T)?

AlphaMissense predicts likely benign (score 0.2141) — an in-silico prediction, not a clinical call.

ACVR1 p.Pro9Leu

c.26C>T · VCV4957127

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2141 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2141	likely benign
REVEL	0.403	indeterminate
SaProt	LLR -3.94	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 25 kb · p 0.034 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACVR1
Protein: p.Pro9Leu
Coding: c.26C>T
MANE Select: NM_001111067
Type: single nucleotide variant
Location: chr2:157799468 (GRCh38)
Gene constraint: LOEUF 0.835 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.70 · 85 PDB

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

Similar variants

ACVR1 p.Pro9Ser Uncertain significance ★★ ⚠ same residue
ACVR1 p.Pro9= 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-pro9leu (accessed [today's date]).

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