Is BMP6 p.Arg94Trp (c.280C>T) pathogenic?

BMP6 p.Arg94Trp (c.280C>T) is classified Conflicting classifications of pathogenicity in BMP6 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-04-01). AlphaMissense: likely pathogenic (0.7048); Rare (popmax 0.332%, mid).

How common is BMP6 p.Arg94Trp (c.280C>T) in the general population?

BMP6 p.Arg94Trp (c.280C>T) is rare (popmax 0.332%, mid) (gnomAD).

What do computational predictors say about BMP6 p.Arg94Trp (c.280C>T)?

AlphaMissense predicts likely pathogenic (score 0.7048) — an in-silico prediction, not a clinical call.

BMP6 p.Arg94Trp

c.280C>T · rs376922072 · VCV2367395

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7048 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.332%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7048	likely pathogenic
REVEL	0.538	indeterminate
SaProt	LLR -12.72	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 0.68, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 152 kb · p 7.1e-05 · regional, not allelic
Overall
CADD	25.5	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 0.332% Middle Eastern · 20/6,026 alleles

Filtering AF 0.22% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.184%

Overall 0.0109% 175/1,606,186 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.332%	301
Remaining individualsnot grpmax-eligible	0.0323%	3,100
Ashkenazi Jewishnot grpmax-eligible	0.017%	5,878
Admixed American	0.0101%	9,899
European (non-Finnish)	0.00985%	10,148
South Asian	0.00552%	18,106
African / African-American	0.00401%	24,927

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.Arg94Trp
Coding: c.280C>T
MANE Select: NM_001718
dbSNP: rs376922072
Type: single nucleotide variant
Location: chr6:7727235 (GRCh38)
Gene constraint: LOEUF 0.523 · pLI 0.94 (gnomAD)
Structure: AlphaFold pLDDT 69.74 · 5 PDB
Residue 94: the 'disordered' region

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

Similar variants

BMP6 p.Leu209Pro Uncertain significance ★★ ⚠ same type
BMP6 p.Ser160= Benign/Likely benign ★★ same type
BMP6 p.Leu137Met Likely pathogenic ★ ⚠ same type
BMP6 c.-377G>A Uncertain significance ★ same type
BMP6 p.Ala142Thr Uncertain significance ★ ⚠ same type
BMP6 p.Ala152Glu Uncertain significance ★ ⚠ same type
BMP6 p.Ala203Ser Uncertain significance ★ ⚠ same type
BMP6 p.Ala254Thr 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/bmp6-p-arg94trp (accessed [today's date]).

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