Is ACVR2B p.Val407Met (c.1219G>A) pathogenic?

ACVR2B p.Val407Met (c.1219G>A) is classified Uncertain significance in ACVR2B (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-05). AlphaMissense: likely benign (0.333); Very rare (popmax 0.00687%, nfe); Associated with heterotaxy, visceral, 4, autosomal.

What condition is associated with ACVR2B p.Val407Met (c.1219G>A)?

ACVR2B p.Val407Met (c.1219G>A) is associated with heterotaxy, visceral, 4, autosomal (ClinVar).

How common is ACVR2B p.Val407Met (c.1219G>A) in the general population?

ACVR2B p.Val407Met (c.1219G>A) is very rare (popmax 0.00687%, nfe) (gnomAD).

What do computational predictors say about ACVR2B p.Val407Met (c.1219G>A)?

AlphaMissense predicts likely benign (score 0.333) — an in-silico prediction, not a clinical call.

ACVR2B p.Val407Met

c.1219G>A · rs750062087 · VCV1386729

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.333 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00687%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

heterotaxy, visceral, 4, autosomal

Computational evidence

Protein change
AlphaMissense	0.333	likely benign
REVEL	0.667	pathogenic-leaning
SaProt	LLR -10.82	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 10	GERP 2, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 4,811 bp · p 9.8e-17 · regional, not allelic
Overall
CADD	32.0	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 0.00687% European (non-Finnish) · 81/1,179,758 alleles

Filtering AF 0.00563% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.00571% 92/1,612,276 alleles · very rare exomes 85/1,461,768 · genomes 7/150,508 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00801%	12,485
European (non-Finnish)grpmax	0.00687%	14,565
African / African-American	0.00539%	18,553
Admixed American	0.00335%	29,869

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ACVR2B
Protein: p.Val407Met
Coding: c.1219G>A
MANE Select: NM_001106
dbSNP: rs750062087
Type: single nucleotide variant
Location: chr3:38482435 (GRCh38)
Gene constraint: LOEUF 0.408 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.18 · 9 PDB
Residue 407: the protein kinase domain

Full ACVR2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

heterotaxy, visceral, 4, autosomal — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACVR2B p.Val407Leu Uncertain significance ★ ⚠ same residue
ACVR2B c.*4984T>C Uncertain significance ★★ same condition
ACVR2B c.*9473T>C Uncertain significance ★★ same condition
ACVR2B p.Arg161Trp Uncertain significance ★★ ⚠ same condition
ACVR2B p.Arg163His Uncertain significance ★★ ⚠ same condition
ACVR2B p.Arg21His Uncertain significance ★★ ⚠ same condition
ACVR2B p.Arg309His Uncertain significance ★★ ⚠ same condition
ACVR2B p.Arg482Gln 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/acvr2b-p-val407met (accessed [today's date]).

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