Is BMP1 p.Arg417Cys (c.1249C>T) pathogenic?

BMP1 p.Arg417Cys (c.1249C>T) is classified Uncertain significance in BMP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-20). AlphaMissense: ambiguous (0.5354); Very rare (popmax 0.00932%, nfe); Associated with osteogenesis imperfecta type 13.

What condition is associated with BMP1 p.Arg417Cys (c.1249C>T)?

BMP1 p.Arg417Cys (c.1249C>T) is associated with osteogenesis imperfecta type 13 (ClinVar).

How common is BMP1 p.Arg417Cys (c.1249C>T) in the general population?

BMP1 p.Arg417Cys (c.1249C>T) is very rare (popmax 0.00932%, nfe) (gnomAD).

How is Osteogenesis imperfecta inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about BMP1 p.Arg417Cys (c.1249C>T)?

AlphaMissense predicts ambiguous (score 0.5354) — an in-silico prediction, not a clinical call.

BMP1 p.Arg417Cys

c.1249C>T · rs147413726 · VCV2078077

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5354 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00932%, nfe)

Conditions

osteogenesis imperfecta type 13

Computational evidence

Protein change
AlphaMissense	0.5354	ambiguous
REVEL	0.406	indeterminate
SaProt	LLR -14.26	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 35 kb · p 1e-07 · regional, not allelic
Overall
CADD	33.0	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 0.00932% European (non-Finnish) · 110/1,179,974 alleles

Filtering AF 0.00791% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00736%

Overall 0.0075% 121/1,613,914 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0096%	10,414
European (non-Finnish)grpmax	0.00932%	10,727
African / African-American	0.00401%	24,968
South Asian	0.0022%	45,528

Remaining individuals 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: BMP1
Protein: p.Arg417Cys
Coding: c.1249C>T
MANE Select: NM_006129
dbSNP: rs147413726
Type: single nucleotide variant
Location: chr8:22194126 (GRCh38)
Gene constraint: LOEUF 0.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.89 · 8 PDB
Residue 417: the cub 1 domain

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

Disease context

osteogenesis imperfecta type 13 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Osteogenesis imperfecta (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: All ages
Prevalence: 1-5 / 10 000 (Worldwide)

Similar variants

BMP1 p.Arg417His Uncertain significance ★ ⚠ same residue
BMP1 p.Cys183Ter Pathogenic/Likely pathogenic ★★ same condition
BMP1 c.*452A>C Uncertain significance ★★ same condition
BMP1 p.Arg152Gln Uncertain significance ★★ ⚠ same condition
BMP1 p.Arg393Gln Uncertain significance ★★ ⚠ same condition
BMP1 p.Arg395Leu Uncertain significance ★★ ⚠ same condition
BMP1 p.Arg562Trp Uncertain significance ★★ ⚠ same condition
BMP1 p.Arg628His 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-arg417cys (accessed [today's date]).

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