Is ACVR1 p.Cys42= (c.126C>T) pathogenic?

ACVR1 p.Cys42= (c.126C>T) is classified Conflicting classifications of pathogenicity in ACVR1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-05). Very rare (popmax 0.00568%, nfe); Associated with fibrodysplasia ossificans progressiva.

What condition is associated with ACVR1 p.Cys42= (c.126C>T)?

ACVR1 p.Cys42= (c.126C>T) is associated with fibrodysplasia ossificans progressiva (ClinVar).

How common is ACVR1 p.Cys42= (c.126C>T) in the general population?

ACVR1 p.Cys42= (c.126C>T) is very rare (popmax 0.00568%, nfe) (gnomAD).

How is Fibrodysplasia ossificans progressiva inherited?

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

ACVR1 p.Cys42=

c.126C>T · rs748424210 · VCV893617

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00568%, nfe)

Conditions

fibrodysplasia ossificans progressiva

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 -2.7	GERP -3.9
Overall
CADD	6.564	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00568% European (non-Finnish) · 67/1,179,982 alleles

Filtering AF 0.00453% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00417%

Overall 0.00496% 80/1,613,814 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00568%	17,612
South Asian	0.00549%	18,211
East Asian	0.00446%	22,431
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
Admixed American	0.00333%	29,987
African / African-American	0.00267%	37,445
Remaining individualsnot grpmax-eligible	0.0016%	62,502

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.Cys42=
Coding: c.126C>T
MANE Select: NM_001111067
dbSNP: rs748424210
Type: single nucleotide variant
Location: chr2:157780542 (GRCh38)
Gene constraint: LOEUF 0.835 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.70 · 85 PDB
Residue 42: 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-cys42 (accessed [today's date]).

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