Is BMP1 p.Leu53Pro (c.158T>C) pathogenic?

BMP1 p.Leu53Pro (c.158T>C) is classified Uncertain significance in BMP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-01). AlphaMissense: likely pathogenic (0.8388); Very rare (popmax 0.00102%, nfe).

How common is BMP1 p.Leu53Pro (c.158T>C) in the general population?

BMP1 p.Leu53Pro (c.158T>C) is very rare (popmax 0.00102%, nfe) (gnomAD).

What do computational predictors say about BMP1 p.Leu53Pro (c.158T>C)?

AlphaMissense predicts likely pathogenic (score 0.8388) — an in-silico prediction, not a clinical call.

BMP1 p.Leu53Pro

c.158T>C · VCV3390270

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8388 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8388	likely pathogenic
REVEL	0.477	indeterminate
SaProt	LLR -7.03	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.6, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 11 kb · p 0.038 · regional, not allelic
Overall
CADD	25.5	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 0.00102% European (non-Finnish) · 12/1,178,600 alleles

Filtering AF 0.000543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000429%

Overall 0.000745% 12/1,610,728 alleles · very rare

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.Leu53Pro
Coding: c.158T>C
MANE Select: NM_006129
Type: single nucleotide variant
Location: chr8:22173611 (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

Similar variants

BMP1 p.Leu53Phe Uncertain significance ★ ⚠ same residue
BMP1 p.Cys183Ter Pathogenic/Likely pathogenic ★★ same type
BMP1 p.Gln70Ter Pathogenic/Likely pathogenic ★★ same type
BMP1 c.1443+6T>C Uncertain significance ★★ same type
BMP1 c.1639+4C>G Uncertain significance ★★ same type
BMP1 c.2233+4C>T Uncertain significance ★★ same type
BMP1 c.*452A>C Uncertain significance ★★ same type
BMP1 p.Ala538Val Uncertain significance ★★ ⚠ same type

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-leu53pro (accessed [today's date]).

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