Is ACVR1 p.His121Arg (c.362A>G) pathogenic?

ACVR1 p.His121Arg (c.362A>G) is classified Uncertain significance in ACVR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-11). AlphaMissense: likely benign (0.0718); Very rare (popmax 0.0022%, sas); Associated with Inborn genetic diseases.

What condition is associated with ACVR1 p.His121Arg (c.362A>G)?

ACVR1 p.His121Arg (c.362A>G) is associated with Inborn genetic diseases (ClinVar).

How common is ACVR1 p.His121Arg (c.362A>G) in the general population?

ACVR1 p.His121Arg (c.362A>G) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about ACVR1 p.His121Arg (c.362A>G)?

AlphaMissense predicts likely benign (score 0.0718) — an in-silico prediction, not a clinical call.

ACVR1 p.His121Arg

c.362A>G · rs1265994310 · VCV2610528

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0718 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0718	likely benign
REVEL	0.169	moderately benign-leaning
SaProt	LLR -6.27	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 2.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 25 kb · p 0.034 · regional, not allelic
Overall
CADD	18.23	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

Grpmax group 0.0022% South Asian · 2/91,058 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000137% 2/1,461,790 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.His121Arg
Coding: c.362A>G
MANE Select: NM_001111067
dbSNP: rs1265994310
Type: single nucleotide variant
Location: chr2:157778312 (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

Disease context

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

Similar variants

ACVR1 p.His121Tyr Uncertain significance ★★ ⚠ same residue
ACVR1 p.Gly328Glu 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.Ile236Leu Uncertain significance ★★ ⚠ same condition
ACVR1 p.Ile352Val 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-his121arg (accessed [today's date]).

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