Is BMP1 p.Pro613Leu (c.1838C>T) pathogenic?

BMP1 p.Pro613Leu (c.1838C>T) is classified Uncertain significance in BMP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-16). AlphaMissense: ambiguous (0.3543); Ultra-rare (popmax 0.0825%, mid).

How common is BMP1 p.Pro613Leu (c.1838C>T) in the general population?

BMP1 p.Pro613Leu (c.1838C>T) is ultra-rare (popmax 0.0825%, mid) (gnomAD).

What do computational predictors say about BMP1 p.Pro613Leu (c.1838C>T)?

AlphaMissense predicts ambiguous (score 0.3543) — an in-silico prediction, not a clinical call.

BMP1 p.Pro613Leu

c.1838C>T · rs374904129 · VCV2191888

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3543 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0825%, mid)

Computational evidence

Protein change
AlphaMissense	0.3543	ambiguous
REVEL	0.348	indeterminate
SaProt	LLR -9.10	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 35 kb · p 1e-07 · regional, not allelic
Overall
CADD	29.2	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 0.0825% Middle Eastern · 5/6,062 alleles

Filtering AF 0.0324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.021%

Overall 0.00157% 23/1,461,866 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0825%	1,212
Remaining individualsnot grpmax-eligible	0.0032%	31,252
African / African-American	0.00133%	75,036
European (non-Finnish)	0.00119%	84,287
South Asian	0.0011%	91,082

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.Pro613Leu
Coding: c.1838C>T
MANE Select: NM_006129
dbSNP: rs374904129
Type: single nucleotide variant
Location: chr8:22196752 (GRCh38)
Gene constraint: LOEUF 0.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.89 · 8 PDB
Residue 613: a disulfide bond; the cub 3 domain

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

Similar variants

BMP1 p.Pro613His Uncertain significance ★★ same residue
BMP1 p.Pro613Arg Uncertain significance ★ ⚠ same residue
BMP1 p.Pro613= Likely benign ★ same residue
BMP1 p.Pro613fs Pathogenic ★ 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

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-pro613leu (accessed [today's date]).

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