Is BMP1 p.Arg586Cys (c.1756C>T) pathogenic?

BMP1 p.Arg586Cys (c.1756C>T) is classified Uncertain significance in BMP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-29). AlphaMissense: ambiguous (0.5548); Very rare (popmax 0.00882%, nfe); Associated with Inborn genetic diseases.

What condition is associated with BMP1 p.Arg586Cys (c.1756C>T)?

BMP1 p.Arg586Cys (c.1756C>T) is associated with Inborn genetic diseases (ClinVar).

How common is BMP1 p.Arg586Cys (c.1756C>T) in the general population?

BMP1 p.Arg586Cys (c.1756C>T) is very rare (popmax 0.00882%, nfe) (gnomAD).

What do computational predictors say about BMP1 p.Arg586Cys (c.1756C>T)?

AlphaMissense predicts ambiguous (score 0.5548) — an in-silico prediction, not a clinical call.

BMP1 p.Arg586Cys

c.1756C>T · rs533843342 · VCV2600180

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5548 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00882%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5548	ambiguous
REVEL	0.654	pathogenic-leaning
SaProt	LLR -12.49	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP -1, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 35 kb · p 1e-07 · regional, not allelic
Overall
CADD	32.0	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 0.00882% European (non-Finnish) · 104/1,179,642 alleles

Filtering AF 0.00741% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00692%

Overall 0.00695% 112/1,612,156 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00882%	11,343
African / African-American	0.00534%	18,729
Admixed American	0.00334%	29,916
Remaining individualsnot grpmax-eligible	0.0016%	62,384
South Asian	0.0011%	91,002

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: BMP1
Protein: p.Arg586Cys
Coding: c.1756C>T
MANE Select: NM_006129
dbSNP: rs533843342
Type: single nucleotide variant
Location: chr8:22195578 (GRCh38)
Gene constraint: LOEUF 0.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.89 · 8 PDB
Residue 586: a disulfide bond; the egf-like 1; calcium-binding domain

Full BMP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BMP1 p.Arg586Ser Uncertain significance ★ ⚠ same residue
BMP1 p.Arg586His Uncertain significance ★★ ⚠ same residue
BMP1 p.Ala657Thr Uncertain significance ★★ ⚠ same condition
BMP1 p.Arg351His Uncertain significance ★★ ⚠ same condition
BMP1 p.Arg351Pro Uncertain significance ★★ ⚠ same condition
BMP1 p.Arg395His Uncertain significance ★★ ⚠ same condition
BMP1 p.Arg508His Uncertain significance ★★ ⚠ same condition
BMP1 p.Arg524Cys Uncertain significance ★★ ⚠ same condition

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/bmp1-p-arg586cys (accessed [today's date]).

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