Is BMP1 p.Ala541= (c.1623C>T) pathogenic?

BMP1 p.Ala541= (c.1623C>T) is classified Conflicting classifications of pathogenicity in BMP1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-28). Ultra-rare (popmax 0.0298%, nfe); Associated with osteogenesis imperfecta type 13.

What condition is associated with BMP1 p.Ala541= (c.1623C>T)?

BMP1 p.Ala541= (c.1623C>T) is associated with osteogenesis imperfecta type 13, osteogenesis imperfecta (ClinVar).

How common is BMP1 p.Ala541= (c.1623C>T) in the general population?

BMP1 p.Ala541= (c.1623C>T) is ultra-rare (popmax 0.0298%, nfe) (gnomAD).

How is Osteogenesis imperfecta inherited?

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

BMP1 p.Ala541=

c.1623C>T · rs181639729 · VCV362585

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0298%, nfe)

Conditions

osteogenesis imperfecta type 13

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.21	donor gain · deltas
Constraint at this position
Conservation	phyloP -9.1	GERP -5.4
Overall
CADD	7.318	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0298% European (non-Finnish) · 351/1,178,150 alleles

Filtering AF 0.0272% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0262%

Overall 0.0242% 390/1,608,752 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0298%	3,357
East Asian	0.0245%	4,077
Finnishnot grpmax-eligible	0.0203%	4,919
Middle Eastern	0.0169%	5,912
Remaining individualsnot grpmax-eligible	0.0129%	7,780
Admixed American	0.00341%	29,294
African / African-American	0.00268%	37,363
South Asian	0.00222%	45,070

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.Ala541=
Coding: c.1623C>T
MANE Select: NM_006129
dbSNP: rs181639729
Type: single nucleotide variant
Location: chr8:22194903 (GRCh38)
Gene constraint: LOEUF 0.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.89 · 8 PDB
Residue 541: the cub 2 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

Also linked: osteogenesis imperfecta

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.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.Arg411His Uncertain significance ★★ ⚠ same condition
BMP1 p.Arg417Cys Uncertain significance ★★ ⚠ same condition
BMP1 p.Arg562Trp 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-ala541 (accessed [today's date]).

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