Is BMP6 p.Pro133Arg (c.398C>G) pathogenic?

BMP6 p.Pro133Arg (c.398C>G) is classified Uncertain significance in BMP6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-16). AlphaMissense: likely pathogenic (0.9666); Very rare (popmax 0.00399%, nfe).

How common is BMP6 p.Pro133Arg (c.398C>G) in the general population?

BMP6 p.Pro133Arg (c.398C>G) is very rare (popmax 0.00399%, nfe) (gnomAD).

What do computational predictors say about BMP6 p.Pro133Arg (c.398C>G)?

AlphaMissense predicts likely pathogenic (score 0.9666) — an in-silico prediction, not a clinical call.

BMP6 p.Pro133Arg

c.398C>G · VCV3991964

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9666 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00399%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9666	likely pathogenic
REVEL	0.891	moderately pathogenic-leaning
SaProt	LLR -8.96	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 152 kb · p 7.1e-05 · regional, not allelic
Overall
CADD	27.3	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 0.00399% European (non-Finnish) · 47/1,178,862 alleles

Filtering AF 0.00307% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00275%

Overall 0.00342% 55/1,609,970 alleles · very rare exomes 47/1,457,802 · genomes 8/152,168 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00399%	25,082
Admixed American	0.00334%	29,906
Remaining individualsnot grpmax-eligible	0.00321%	31,126
African / African-American	0.00268%	37,343
East Asian	0.00223%	44,756
South Asian	0.0011%	90,846

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.Pro133Arg
Coding: c.398C>G
MANE Select: NM_001718
Type: single nucleotide variant
Location: chr6:7727353 (GRCh38)
Gene constraint: LOEUF 0.523 · pLI 0.94 (gnomAD)
Structure: AlphaFold pLDDT 69.74 · 5 PDB

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

Similar variants

BMP6 p.Pro133Ser 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-pro133arg (accessed [today's date]).

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