Is BMP6 p.Arg257His (c.770G>A) pathogenic?

BMP6 p.Arg257His (c.770G>A) is classified Likely benign in BMP6 (ClinVar, Single submitter, 2 submitters; last evaluated 2026-04-01). AlphaMissense: ambiguous (0.5165); Low-frequency (popmax 1.07%, afr); Associated with iron overload, susceptibility to.

What condition is associated with BMP6 p.Arg257His (c.770G>A)?

BMP6 p.Arg257His (c.770G>A) is associated with iron overload, susceptibility to (ClinVar).

How common is BMP6 p.Arg257His (c.770G>A) in the general population?

BMP6 p.Arg257His (c.770G>A) is low-frequency (popmax 1.07%, afr) (gnomAD).

What do computational predictors say about BMP6 p.Arg257His (c.770G>A)?

AlphaMissense predicts ambiguous (score 0.5165) — an in-silico prediction, not a clinical call.

BMP6 p.Arg257His

c.770G>A · rs148916269 · VCV1801219

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5165 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.07%, afr)

Conditions

iron overload, susceptibility to

Computational evidence

Protein change
AlphaMissense	0.5165	ambiguous
REVEL	0.637	indeterminate
SaProt	LLR -10.15	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 152 kb · p 7.1e-05 · regional, not allelic
Overall
CADD	31.0	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 1.07% African / African-American · 800/75,026 alleles

Filtering AF 1.01% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.981%

Overall 0.076% 1,227/1,614,048 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.07%	94
Middle Eastern	0.264%	379
Admixed American	0.172%	583
Remaining individualsnot grpmax-eligible	0.13%	772
Ashkenazi Jewishnot grpmax-eligible	0.0338%	2,961
South Asian	0.0176%	5,692
European (non-Finnish)	0.0166%	6,020
East Asian	0.00891%	11,220
Finnishnot grpmax-eligible	0.00156%	64,028

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.Arg257His
Coding: c.770G>A
MANE Select: NM_001718
dbSNP: rs148916269
Type: single nucleotide variant
Location: chr6:7845245 (GRCh38)
Gene constraint: LOEUF 0.523 · pLI 0.94 (gnomAD)
Structure: AlphaFold pLDDT 69.74 · 5 PDB
Residue 257: a UniProt-annotated variant site (in io; associated with disease susceptibility); a UniProt-annotated variant site (in)

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.Gln113Glu Benign ★ ⚠ same condition
BMP6 p.Leu96Pro Likely 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-arg257his (accessed [today's date]).

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