Is BMP1 p.Cys559Ser (c.1676G>C) pathogenic?

BMP1 p.Cys559Ser (c.1676G>C) is classified Uncertain significance in BMP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-02). AlphaMissense: likely pathogenic (0.9997); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with BMP1 p.Cys559Ser (c.1676G>C)?

BMP1 p.Cys559Ser (c.1676G>C) is associated with Inborn genetic diseases (ClinVar).

How common is BMP1 p.Cys559Ser (c.1676G>C) in the general population?

BMP1 p.Cys559Ser (c.1676G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BMP1 p.Cys559Ser (c.1676G>C)?

AlphaMissense predicts likely pathogenic (score 0.9997) — an in-silico prediction, not a clinical call.

BMP1 p.Cys559Ser

c.1676G>C · rs2539013408 · VCV2332293

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9997 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9997	likely pathogenic · top 2% in BMP1
REVEL	0.916	moderately pathogenic-leaning
SaProt	LLR -16.23	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 35 kb · p 1e-07 · regional, not allelic
Overall
CADD	27.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BMP1
Protein: p.Cys559Ser
Coding: c.1676G>C
MANE Select: NM_006129
dbSNP: rs2539013408
Type: single nucleotide variant
Location: chr8:22195498 (GRCh38)
Gene constraint: LOEUF 0.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.89 · 8 PDB
Residue 559: 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.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
BMP1 p.Arg562Trp Uncertain significance ★★ ⚠ same condition
BMP1 p.Arg628Cys 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-cys559ser (accessed [today's date]).

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