Is BMP6 p.Pro95Leu (c.284C>T) pathogenic?

BMP6 p.Pro95Leu (c.284C>T) is classified Uncertain significance in BMP6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-12). AlphaMissense: ambiguous (0.5499); Very rare (popmax 0.00168%, amr).

How common is BMP6 p.Pro95Leu (c.284C>T) in the general population?

BMP6 p.Pro95Leu (c.284C>T) is very rare (popmax 0.00168%, amr) (gnomAD).

What do computational predictors say about BMP6 p.Pro95Leu (c.284C>T)?

AlphaMissense predicts ambiguous (score 0.5499) — an in-silico prediction, not a clinical call.

BMP6 p.Pro95Leu

c.284C>T · rs750246590 · VCV2602464

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5499 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00168%, amr)

Computational evidence

Protein change
AlphaMissense	0.5499	ambiguous
REVEL	0.621	indeterminate
SaProt	LLR -9.26	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 1.6, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 152 kb · p 7.1e-05 · regional, not allelic
Overall
CADD	28.2	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 0.00168% Admixed American · 1/59,418 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000832%

Overall 0.00137% 22/1,606,424 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00168%	59,418
European (non-Finnish)	0.00161%	61,960
Remaining individualsnot grpmax-eligible	0.00161%	62,024
African / African-American	0.00134%	74,804

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.Pro95Leu
Coding: c.284C>T
MANE Select: NM_001718
dbSNP: rs750246590
Type: single nucleotide variant
Location: chr6:7727239 (GRCh38)
Gene constraint: LOEUF 0.523 · pLI 0.94 (gnomAD)
Structure: AlphaFold pLDDT 69.74 · 5 PDB
Residue 95: a UniProt-annotated variant site (in io; associated with disease susceptibility; some patients also carry a hfe variant; decreased function in positive regulation of smad protein signal transduction; results in partial activation of hepcidin expression; affects post-translational processing resulting in reduced amount of the mature form; results in impaired secretion); the 'disordered' region

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

Similar variants

BMP6 p.Pro95Ser Likely benign ★ same residue
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

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-pro95leu (accessed [today's date]).

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