Is ACVR1 p.Leu196Pro (c.587T>C) pathogenic?

ACVR1 p.Leu196Pro (c.587T>C) is classified Pathogenic in ACVR1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2014-01-01). AlphaMissense: likely pathogenic (0.9938); Absent from gnomAD v4.1; Associated with fibrodysplasia ossificans progressiva.

What condition is associated with ACVR1 p.Leu196Pro (c.587T>C)?

ACVR1 p.Leu196Pro (c.587T>C) is associated with fibrodysplasia ossificans progressiva (ClinVar).

How common is ACVR1 p.Leu196Pro (c.587T>C) in the general population?

ACVR1 p.Leu196Pro (c.587T>C) is absent from gnomAD v4.1 (gnomAD).

How is Fibrodysplasia ossificans progressiva inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ACVR1 p.Leu196Pro (c.587T>C)?

AlphaMissense predicts likely pathogenic (score 0.9938) — an in-silico prediction, not a clinical call.

ACVR1 p.Leu196Pro

c.587T>C · rs797045135 · VCV208843

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9938 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

fibrodysplasia ossificans progressiva

Computational evidence

Protein change
AlphaMissense	0.9938	likely pathogenic ✓ concordant with ClinVar
REVEL	0.965	strongly pathogenic-leaning
SaProt	LLR -13.50	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 11	GERP 2.8, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 13 kb · p 3.6e-12 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

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.Leu196Pro
Coding: c.587T>C
MANE Select: NM_001111067
dbSNP: rs797045135
Type: single nucleotide variant
Location: chr2:157774144 (GRCh38)
Gene constraint: LOEUF 0.835 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.70 · 85 PDB
Residue 196: a β-strand; the gs domain

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

Disease context

fibrodysplasia ossificans progressiva — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Fibrodysplasia ossificans progressiva (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Childhood
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

ACVR1 p.Leu196= Likely benign ★ same residue
ACVR1 p.Arg206His Pathogenic ★★ same condition
ACVR1 p.Gly328Glu Pathogenic/Likely pathogenic ★★ same condition
ACVR1 p.Gly356Asp Pathogenic/Likely pathogenic ★★ same condition
ACVR1 p.Ser41Phe Uncertain significance ★★ ⚠ same condition
ACVR1 c.1395+5G>A Likely benign ★★ same condition
ACVR1 c.643+7C>T Benign ★★ same condition
ACVR1 c.644-3T>C Benign/Likely benign ★★ 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/acvr1-p-leu196pro (accessed [today's date]).

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