Is BMP6 p.Val394Met (c.1180G>A) pathogenic?

BMP6 p.Val394Met (c.1180G>A) is classified Likely benign in BMP6 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-08-12). AlphaMissense: likely benign (0.0943); Ultra-rare (popmax 0.085%, nfe); Associated with BMP6-related disorder.

What condition is associated with BMP6 p.Val394Met (c.1180G>A)?

BMP6 p.Val394Met (c.1180G>A) is associated with BMP6-related disorder (ClinVar).

How common is BMP6 p.Val394Met (c.1180G>A) in the general population?

BMP6 p.Val394Met (c.1180G>A) is ultra-rare (popmax 0.085%, nfe) (gnomAD).

What do computational predictors say about BMP6 p.Val394Met (c.1180G>A)?

AlphaMissense predicts likely benign (score 0.0943) — an in-silico prediction, not a clinical call.

BMP6 p.Val394Met

c.1180G>A · VCV3352424

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0943 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.085%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

BMP6-related disorder

Computational evidence

Protein change
AlphaMissense	0.0943	likely benign
REVEL	0.218	benign-leaning
SaProt	LLR -7.25	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 2.6	GERP -1.6, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 152 kb · p 7.1e-05 · regional, not allelic
Overall
CADD	21.4	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 0.085% European (non-Finnish) · 1,003/1,180,028 alleles

Filtering AF 0.0806% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0789%

Overall 0.067% 1,082/1,614,126 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.219%	456
European (non-Finnish)grpmax	0.085%	1,176
Remaining individualsnot grpmax-eligible	0.048%	2,083
Admixed American	0.0217%	4,618
South Asian	0.0198%	5,060
African / African-American	0.012%	8,340
Finnishnot grpmax-eligible	0.0109%	9,145

Amish 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: BMP6
Protein: p.Val394Met
Coding: c.1180G>A
MANE Select: NM_001718
Type: single nucleotide variant
Location: chr6:7862474 (GRCh38)
Gene constraint: LOEUF 0.523 · pLI 0.94 (gnomAD)
Structure: AlphaFold pLDDT 69.74 · 5 PDB
Residue 394: a UniProt-annotated variant site (in io; associated with disease susceptibility); a UniProt-annotated variant site (in io; associated with disease susceptibility; results in decreased activation of hepcidin expression in cultured liver cells); the 'disordered' region

Full BMP6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

BMP6-related disorder

Similar variants

BMP6 c.1392+7T>G Likely benign same condition
BMP6 c.665-3T>C Likely benign same condition
BMP6 p.Ala189= Likely benign same condition
BMP6 p.Ala189Thr Benign same condition
BMP6 p.Ala212= Benign same condition
BMP6 p.Ala343= Benign same condition
BMP6 p.Arg28Gln Benign same condition
BMP6 p.Arg396= Likely benign 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/bmp6-p-val394met (accessed [today's date]).

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