Is BMP6 p.Pro95Ser (c.283C>T) pathogenic?

BMP6 p.Pro95Ser (c.283C>T) is classified Likely benign in BMP6 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-08-01). AlphaMissense: ambiguous (0.473); Ultra-rare (popmax 0.0667%, mid); Associated with iron overload, susceptibility to.

What condition is associated with BMP6 p.Pro95Ser (c.283C>T)?

BMP6 p.Pro95Ser (c.283C>T) is associated with iron overload, susceptibility to (ClinVar).

How common is BMP6 p.Pro95Ser (c.283C>T) in the general population?

BMP6 p.Pro95Ser (c.283C>T) is ultra-rare (popmax 0.0667%, mid) (gnomAD).

What do computational predictors say about BMP6 p.Pro95Ser (c.283C>T)?

AlphaMissense predicts ambiguous (score 0.473) — an in-silico prediction, not a clinical call.

BMP6 p.Pro95Ser

c.283C>T · rs199518216 · VCV1801214

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.473 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0667%, mid)

Conditions

iron overload, susceptibility to

Computational evidence

Protein change
AlphaMissense	0.473	ambiguous
REVEL	0.373	indeterminate
SaProt	LLR -9.19	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.5	GERP 0.68, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 152 kb · p 7.1e-05 · regional, not allelic
Overall
CADD	25.6	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 0.0667% Middle Eastern · 4/6,000 alleles

Filtering AF 0.0518% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.047%

Overall 0.0327% 526/1,606,518 alleles · ultra-rare exomes 499/1,454,206 · genomes 27/152,312 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.768%	130
Middle Easterngrpmax	0.0667%	1,500
South Asian	0.0652%	1,535
European (non-Finnish)	0.0352%	2,844
Admixed American	0.032%	3,129
Remaining individualsnot grpmax-eligible	0.0193%	5,171
East Asian	0.00672%	14,878
African / African-American	0.00667%	14,982
Finnishnot grpmax-eligible	0.00489%	20,467

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro95Ser
Coding: c.283C>T
MANE Select: NM_001718
dbSNP: rs199518216
Type: single nucleotide variant
Location: chr6:7727238 (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

Disease context

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

Similar variants

BMP6 p.Pro95Leu Uncertain significance ★ same residue
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.Leu96Pro Likely benign ★ same condition
BMP6 p.Ser160= Benign/Likely benign ★★ 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-pro95ser (accessed [today's date]).

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