Is ACVR1 p.Cys35Arg (c.103T>C) pathogenic?

ACVR1 p.Cys35Arg (c.103T>C) is classified Uncertain significance in ACVR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely pathogenic (0.9988); Very rare (popmax 8.47e-05%, nfe); Associated with fibrodysplasia ossificans progressiva.

What condition is associated with ACVR1 p.Cys35Arg (c.103T>C)?

ACVR1 p.Cys35Arg (c.103T>C) is associated with fibrodysplasia ossificans progressiva (ClinVar).

How common is ACVR1 p.Cys35Arg (c.103T>C) in the general population?

ACVR1 p.Cys35Arg (c.103T>C) is very rare (popmax 8.47e-05%, nfe) (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.Cys35Arg (c.103T>C)?

AlphaMissense predicts likely pathogenic (score 0.9988) — an in-silico prediction, not a clinical call.

ACVR1 p.Cys35Arg

c.103T>C · VCV4278067

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9988 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

fibrodysplasia ossificans progressiva

Computational evidence

Protein change
AlphaMissense	0.9988	likely pathogenic · top 6% in ACVR1
REVEL	0.971	strongly pathogenic-leaning
SaProt	LLR -18.48	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 1.9, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 25 kb · p 0.034 · regional, not allelic
Overall
CADD	28.0	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 8.47e-05% European (non-Finnish) · 1/1,179,968 alleles

Overall 6.84e-05% 1/1,461,884 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.Cys35Arg
Coding: c.103T>C
MANE Select: NM_001111067
Type: single nucleotide variant
Location: chr2:157780565 (GRCh38)
Gene constraint: LOEUF 0.835 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.70 · 85 PDB
Residue 35: a β-strand

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.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
ACVR1 c.68-25T>C 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-cys35arg (accessed [today's date]).

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