Is BMP6 p.Leu96Pro (c.287T>C) pathogenic?

BMP6 p.Leu96Pro (c.287T>C) is classified Likely benign in BMP6 (ClinVar, Single submitter, 3 submitters; last evaluated 2025-08-01). AlphaMissense: likely benign (0.1045); Rare (popmax 0.741%, nfe); Associated with iron overload, susceptibility to.

What condition is associated with BMP6 p.Leu96Pro (c.287T>C)?

BMP6 p.Leu96Pro (c.287T>C) is associated with iron overload, susceptibility to (ClinVar).

How common is BMP6 p.Leu96Pro (c.287T>C) in the general population?

BMP6 p.Leu96Pro (c.287T>C) is rare (popmax 0.741%, nfe) (gnomAD).

What do computational predictors say about BMP6 p.Leu96Pro (c.287T>C)?

AlphaMissense predicts likely benign (score 0.1045) — an in-silico prediction, not a clinical call.

BMP6 p.Leu96Pro

c.287T>C · rs200573175 · VCV1801215

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1045 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.741%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

iron overload, susceptibility to

Computational evidence

Protein change
AlphaMissense	0.1045	likely benign
REVEL	0.287	benign-leaning
SaProt	LLR -6.18	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 5.7	GERP 1.3, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 152 kb · p 7.1e-05 · regional, not allelic
Overall
CADD	23.6	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 0.741% European (non-Finnish) · 8,727/1,177,212 alleles

Filtering AF 0.728% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.723%

Overall 0.594% 9,551/1,606,568 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.741%	135
Remaining individualsnot grpmax-eligible	0.474%	211
Admixed American	0.338%	296
Middle Eastern	0.3%	333
Finnishnot grpmax-eligible	0.254%	394
Ashkenazi Jewishnot grpmax-eligible	0.18%	555
African / African-American	0.116%	861
Amishnot grpmax-eligible	0.11%	912
South Asian	0.0155%	6,468

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.Leu96Pro
Coding: c.287T>C
MANE Select: NM_001718
dbSNP: rs200573175
Type: single nucleotide variant
Location: chr6:7727242 (GRCh38)
Gene constraint: LOEUF 0.523 · pLI 0.94 (gnomAD)
Structure: AlphaFold pLDDT 69.74 · 5 PDB
Residue 96: 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

Disease context

iron overload, susceptibility to — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BMP6 p.Leu209Pro Uncertain significance ★★ ⚠ same condition
BMP6 p.Ile83Val Uncertain significance ★ ⚠ same condition
BMP6 p.Pro199Ala Uncertain significance ★ ⚠ same condition
BMP6 p.Arg257His Likely benign ★ same condition
BMP6 p.Gln113Glu Benign ★ same condition
BMP6 p.Pro95Ser Likely benign ★ same condition
BMP6 p.Ser160= Benign/Likely benign ★★ same type
BMP6 p.Leu137Met Likely pathogenic ★ ⚠ 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-leu96pro (accessed [today's date]).

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