Is BMP6 p.Leu187Phe (c.559C>T) pathogenic?

BMP6 p.Leu187Phe (c.559C>T) is classified Uncertain significance in BMP6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-04). AlphaMissense: likely benign (0.0632); Very rare (popmax 0.00448%, eas).

How common is BMP6 p.Leu187Phe (c.559C>T) in the general population?

BMP6 p.Leu187Phe (c.559C>T) is very rare (popmax 0.00448%, eas) (gnomAD).

What do computational predictors say about BMP6 p.Leu187Phe (c.559C>T)?

AlphaMissense predicts likely benign (score 0.0632) — an in-silico prediction, not a clinical call.

BMP6 p.Leu187Phe

c.559C>T · VCV3481171

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0632 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00448%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0632	likely benign
REVEL	0.245	benign-leaning
SaProt	LLR -7.95	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 0.68	GERP 0.81, phastCons 0.82
Regional constraint	o/e 1.17	unconstrained · MANE · 152 kb · p 7.1e-05 · regional, not allelic
Overall
CADD	20.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00448% East Asian · 2/44,674 alleles

Filtering AF 0.00189% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.00244% 39/1,596,166 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00448%	22,337
Remaining individualsnot grpmax-eligible	0.00322%	31,053
African / African-American	0.00268%	37,365
European (non-Finnish)	0.00263%	37,988
South Asian	0.00222%	45,095

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.Leu187Phe
Coding: c.559C>T
MANE Select: NM_001718
Type: single nucleotide variant
Location: chr6:7727514 (GRCh38)
Gene constraint: LOEUF 0.523 · pLI 0.94 (gnomAD)
Structure: AlphaFold pLDDT 69.74 · 5 PDB
Residue 187: a UniProt-annotated variant site (in io; associated with disease susceptibility); 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-leu187phe (accessed [today's date]).

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