Is BMP6 p.Phe208Ser (c.623T>C) pathogenic?

BMP6 p.Phe208Ser (c.623T>C) is classified Uncertain significance in BMP6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-09). AlphaMissense: likely pathogenic (0.8257); Ultra-rare (popmax 0.037%, amr).

How common is BMP6 p.Phe208Ser (c.623T>C) in the general population?

BMP6 p.Phe208Ser (c.623T>C) is ultra-rare (popmax 0.037%, amr) (gnomAD).

What do computational predictors say about BMP6 p.Phe208Ser (c.623T>C)?

AlphaMissense predicts likely pathogenic (score 0.8257) — an in-silico prediction, not a clinical call.

BMP6 p.Phe208Ser

c.623T>C · rs750654076 · VCV2391850

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8257 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.037%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8257	likely pathogenic
REVEL	0.519	indeterminate
SaProt	LLR -10.77	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 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 152 kb · p 7.1e-05 · regional, not allelic
Overall
CADD	28.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.037% Admixed American · 21/56,766 alleles

Filtering AF 0.0248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0208%

Overall 0.00196% 31/1,582,374 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.037%	2,703
Remaining individualsnot grpmax-eligible	0.0114%	8,801
African / African-American	0.00271%	36,847
European (non-Finnish)	8.52e-05%	1,173,316

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.Phe208Ser
Coding: c.623T>C
MANE Select: NM_001718
dbSNP: rs750654076
Type: single nucleotide variant
Location: chr6:7727578 (GRCh38)
Gene constraint: LOEUF 0.523 · pLI 0.94 (gnomAD)
Structure: AlphaFold pLDDT 69.74 · 5 PDB
Residue 208: a UniProt-annotated variant site (in io; associated with disease susceptibility)

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

Similar variants

BMP6 p.Phe208Leu Uncertain significance ★ ⚠ 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-phe208ser (accessed [today's date]).

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