Is BMPR1B p.Pro451= (c.1353C>A) pathogenic?

BMPR1B p.Pro451= (c.1353C>A) is classified Likely benign in BMPR1B (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-07). Ultra-rare (popmax 0.0277%, sas); Associated with brachydactyly type A2.

What condition is associated with BMPR1B p.Pro451= (c.1353C>A)?

BMPR1B p.Pro451= (c.1353C>A) is associated with brachydactyly type A2, acromesomelic dysplasia 3 (ClinVar).

How common is BMPR1B p.Pro451= (c.1353C>A) in the general population?

BMPR1B p.Pro451= (c.1353C>A) is ultra-rare (popmax 0.0277%, sas) (gnomAD).

BMPR1B p.Pro451=

c.1353C>A · rs551844397 · VCV1589840

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0277%, sas)

Conditions

brachydactyly type A2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.24	GERP -2.1, phastCons 0.23
Overall
CADD	7.701	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0277% South Asian · 25/90,100 alleles

Filtering AF 0.0193% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0164%

Overall 0.00267% 43/1,610,990 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0277%	3,604
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,524
Remaining individualsnot grpmax-eligible	0.0016%	62,382
European (non-Finnish)	0.00136%	73,664

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: BMPR1B
Protein: p.Pro451=
Coding: c.1353C>A
MANE Select: NM_001203
dbSNP: rs551844397
Type: single nucleotide variant
Location: chr4:95152743 (GRCh38)
Gene constraint: LOEUF 0.331 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.36 · 1 PDB
Residue 451: an α-helix; the protein kinase domain

Full BMPR1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

brachydactyly type A2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: acromesomelic dysplasia 3

Similar variants

BMPR1B c.585+1G>C Likely pathogenic ★★ same condition
BMPR1B p.Arg486Trp Pathogenic ★★ same condition
BMPR1B p.Arg412Gly Uncertain significance ★★ ⚠ same condition
BMPR1B p.Arg91Ile Uncertain significance ★★ ⚠ same condition
BMPR1B p.Asn257Asp Uncertain significance ★★ ⚠ same condition
BMPR1B p.Asp166Gly Uncertain significance ★★ ⚠ same condition
BMPR1B p.Asp280Asn Uncertain significance ★★ same condition
BMPR1B p.Asp365Asn 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/bmpr1b-p-pro451 (accessed [today's date]).

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