Is BMP1 p.Arg76Trp (c.226C>T) pathogenic?

BMP1 p.Arg76Trp (c.226C>T) is classified Uncertain significance in BMP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-26). AlphaMissense: likely benign (0.0951); Very rare (popmax 0.00882%, nfe); Associated with osteogenesis imperfecta.

What condition is associated with BMP1 p.Arg76Trp (c.226C>T)?

BMP1 p.Arg76Trp (c.226C>T) is associated with osteogenesis imperfecta (ClinVar).

How common is BMP1 p.Arg76Trp (c.226C>T) in the general population?

BMP1 p.Arg76Trp (c.226C>T) is very rare (popmax 0.00882%, 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.Arg76Trp (c.226C>T)?

AlphaMissense predicts likely benign (score 0.0951) — an in-silico prediction, not a clinical call.

BMP1 p.Arg76Trp

c.226C>T · rs201377252 · VCV1702067

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0951 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00882%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

osteogenesis imperfecta

Computational evidence

Protein change
AlphaMissense	0.0951	likely benign
REVEL	0.097	moderately benign-leaning
SaProt	LLR -8.86	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -1, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 11 kb · p 0.038 · regional, not allelic
Overall
CADD	21.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00882% European (non-Finnish) · 104/1,179,684 alleles

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

Overall 0.00762% 123/1,613,620 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0144%	6,943
European (non-Finnish)grpmax	0.00882%	11,343
African / African-American	0.00533%	18,758
South Asian	0.00439%	22,759
Finnishnot grpmax-eligible	0.00312%	32,019

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.Arg76Trp
Coding: c.226C>T
MANE Select: NM_006129
dbSNP: rs201377252
Type: single nucleotide variant
Location: chr8:22173679 (GRCh38)
Gene constraint: LOEUF 0.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.89 · 8 PDB

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

Disease context

osteogenesis imperfecta — 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.Arg76Gln Likely benign ★ same residue
BMP1 p.Arg411His Uncertain significance ★★ ⚠ same condition
BMP1 p.Pro816Ala Uncertain significance ★★ ⚠ same condition
BMP1 p.Ser692Phe Uncertain significance ★★ ⚠ same condition
BMP1 c.1766-5C>T Benign ★★ same condition
BMP1 p.Arg314His Benign/Likely benign ★★ ⚠ same condition
BMP1 p.Arg371His Benign/Likely benign ★★ ⚠ same condition
BMP1 p.Asp705= Benign ★★ 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-arg76trp (accessed [today's date]).

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