Is ACVR1 p.Ser41Phe (c.122C>T) pathogenic?

ACVR1 p.Ser41Phe (c.122C>T) is classified Uncertain significance in ACVR1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-12). AlphaMissense: likely benign (0.2447); Ultra-rare (popmax 0.0164%, mid); Associated with Inborn genetic diseases.

What condition is associated with ACVR1 p.Ser41Phe (c.122C>T)?

ACVR1 p.Ser41Phe (c.122C>T) is associated with Inborn genetic diseases, fibrodysplasia ossificans progressiva (ClinVar).

How common is ACVR1 p.Ser41Phe (c.122C>T) in the general population?

ACVR1 p.Ser41Phe (c.122C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about ACVR1 p.Ser41Phe (c.122C>T)?

AlphaMissense predicts likely benign (score 0.2447) — an in-silico prediction, not a clinical call.

ACVR1 p.Ser41Phe

c.122C>T · rs55957214 · VCV893905

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2447 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2447	likely benign
REVEL	0.685	pathogenic-leaning
SaProt	LLR -7.08	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 25 kb · p 0.034 · regional, not allelic
Overall
CADD	25.1	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

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.0013% 21/1,613,800 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Finnishnot grpmax-eligible	0.00156%	63,990
European (non-Finnish)	0.00153%	65,555
African / African-American	0.00134%	74,814

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.Ser41Phe
Coding: c.122C>T
MANE Select: NM_001111067
dbSNP: rs55957214
Type: single nucleotide variant
Location: chr2:157780546 (GRCh38)
Gene constraint: LOEUF 0.835 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.70 · 85 PDB
Residue 41: a UniProt-annotated variant site (in)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: fibrodysplasia ossificans progressiva

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.Arg147Gln Uncertain significance ★★ ⚠ same condition
ACVR1 p.Arg307Gln Uncertain significance ★★ ⚠ same condition
ACVR1 p.Arg417Gln Uncertain significance ★★ ⚠ same condition
ACVR1 p.Gly39Val Uncertain significance ★★ ⚠ same condition
ACVR1 p.His121Tyr Uncertain significance ★★ ⚠ 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-ser41phe (accessed [today's date]).

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