Is ACVR1C p.Ile249Val (c.745A>G) pathogenic?

ACVR1C p.Ile249Val (c.745A>G) is classified Uncertain significance in ACVR1C (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-26). AlphaMissense: likely benign (0.1958); Very rare (popmax 0.00356%, nfe).

How common is ACVR1C p.Ile249Val (c.745A>G) in the general population?

ACVR1C p.Ile249Val (c.745A>G) is very rare (popmax 0.00356%, nfe) (gnomAD).

What do computational predictors say about ACVR1C p.Ile249Val (c.745A>G)?

AlphaMissense predicts likely benign (score 0.1958) — an in-silico prediction, not a clinical call.

ACVR1C p.Ile249Val

c.745A>G · VCV3485410

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1958 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00356%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1958	likely benign
REVEL	0.685	pathogenic-leaning
SaProt	LLR -8.50	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 5.1	GERP 0.72, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 95 kb · p 2.1e-07 · regional, not allelic
Overall
CADD	22.9	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 0.00356% European (non-Finnish) · 42/1,180,024 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.00273% 44/1,613,990 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00356%	28,096
Finnishnot grpmax-eligible	0.00312%	32,006

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: ACVR1C
Protein: p.Ile249Val
Coding: c.745A>G
MANE Select: NM_145259
Type: single nucleotide variant
Location: chr2:157550192 (GRCh38)
Gene constraint: LOEUF 0.6 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 85.35
Residue 249: the protein kinase domain

Full ACVR1C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACVR1C c.1226-50T>C Benign ★★ same type
ACVR1C c.1356+6G>C Benign ★★ same type
ACVR1C c.305-34T>C Benign ★★ same type
ACVR1C c.544+63A>G Benign ★★ same type
ACVR1C c.73+9C>A Benign ★★ same type
ACVR1C c.776-13A>G Benign ★★ same type
ACVR1C c.943+49G>A Benign ★★ same type
ACVR1C p.Asn150His Benign ★★ 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/acvr1c-p-ile249val (accessed [today's date]).

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