Is ACVR1B p.Ser237Cys (c.710C>G) pathogenic?

ACVR1B p.Ser237Cys (c.710C>G) is classified Uncertain significance in ACVR1B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). AlphaMissense: likely pathogenic (0.7513); Very rare (popmax 6.84e-05%).

How common is ACVR1B p.Ser237Cys (c.710C>G) in the general population?

ACVR1B p.Ser237Cys (c.710C>G) is very rare (popmax 6.84e-05%) (gnomAD).

What do computational predictors say about ACVR1B p.Ser237Cys (c.710C>G)?

AlphaMissense predicts likely pathogenic (score 0.7513) — an in-silico prediction, not a clinical call.

ACVR1B p.Ser237Cys

c.710C>G · VCV4223579

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7513 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7513	likely pathogenic
REVEL	0.851	moderately pathogenic-leaning
SaProt	LLR -12.06	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 15 kb · p 3.8e-33 · regional, not allelic
Overall
CADD	32.0	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 6.84e-05%

Overall 6.84e-05% 1/1,461,890 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: ACVR1B
Protein: p.Ser237Cys
Coding: c.710C>G
MANE Select: NM_004302
Type: single nucleotide variant
Location: chr12:51981098 (GRCh38)
Gene constraint: LOEUF 0.403 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.09 · 2 PDB
Residue 237: the protein kinase domain

Full ACVR1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACVR1B p.Leu494= Benign ★★ same type
ACVR1B c.812-1205T>G Uncertain significance ★ same type
ACVR1B c.812-1213A>C Uncertain significance ★ same type
ACVR1B c.812-1220G>A Uncertain significance ★ same type
ACVR1B c.812-1246C>A Uncertain significance ★ same type
ACVR1B c.812-1263G>T Uncertain significance ★ same type
ACVR1B c.812-1299C>T Uncertain significance ★ same type
ACVR1B p.Ala35Thr Uncertain significance ★ ⚠ same type

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/acvr1b-p-ser237cys (accessed [today's date]).

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