Is BMP1 p.Pro613His (c.1838C>A) pathogenic?

BMP1 p.Pro613His (c.1838C>A) is classified Uncertain significance in BMP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-03-02). AlphaMissense: ambiguous (0.5251); Very rare (popmax 0.00415%, nfe).

How common is BMP1 p.Pro613His (c.1838C>A) in the general population?

BMP1 p.Pro613His (c.1838C>A) is very rare (popmax 0.00415%, nfe) (gnomAD).

What do computational predictors say about BMP1 p.Pro613His (c.1838C>A)?

AlphaMissense predicts ambiguous (score 0.5251) — an in-silico prediction, not a clinical call.

BMP1 p.Pro613His

c.1838C>A · rs374904129 · VCV1331206

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5251 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00415%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5251	ambiguous
REVEL	0.316	indeterminate
SaProt	LLR -8.24	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	26.7	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 0.00415% European (non-Finnish) · 49/1,180,026 alleles

Filtering AF 0.00318% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00286%

Overall 0.00341% 55/1,614,006 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,828
European (non-Finnish)grpmax	0.00415%	24,082
East Asian	0.00223%	44,868
South Asian	0.0022%	45,543

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.Pro613His
Coding: c.1838C>A
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.Pro613Arg Uncertain significance ★ ⚠ same residue
BMP1 p.Pro613Leu 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-pro613his (accessed [today's date]).

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