Is BMP1 p.Ser458Arg (c.1374C>A) pathogenic?

BMP1 p.Ser458Arg (c.1374C>A) is classified Uncertain significance in BMP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-03). AlphaMissense: likely pathogenic (0.8087); Very rare (popmax 0.000678%, nfe); Associated with Inborn genetic diseases.

What condition is associated with BMP1 p.Ser458Arg (c.1374C>A)?

BMP1 p.Ser458Arg (c.1374C>A) is associated with Inborn genetic diseases (ClinVar).

How common is BMP1 p.Ser458Arg (c.1374C>A) in the general population?

BMP1 p.Ser458Arg (c.1374C>A) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about BMP1 p.Ser458Arg (c.1374C>A)?

AlphaMissense predicts likely pathogenic (score 0.8087) — an in-silico prediction, not a clinical call.

BMP1 p.Ser458Arg

c.1374C>A · rs2539011272 · VCV3134495

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8087 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8087	likely pathogenic
REVEL	0.15	moderately benign-leaning
SaProt	LLR -7.16	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 2.6, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 35 kb · p 1e-07 · regional, not allelic
Overall
CADD	27.9	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 0.000678% European (non-Finnish) · 8/1,180,034 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000547% 8/1,461,890 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.Ser458Arg
Coding: c.1374C>A
MANE Select: NM_006129
dbSNP: rs2539011272
Type: single nucleotide variant
Location: chr8:22194521 (GRCh38)
Gene constraint: LOEUF 0.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.89 · 8 PDB
Residue 458: a disulfide bond; the cub 2 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BMP1 p.Ser458Ile Uncertain significance ★ ⚠ same residue
BMP1 p.Ala657Thr Uncertain significance ★★ ⚠ same condition
BMP1 p.Arg351His Uncertain significance ★★ ⚠ same condition
BMP1 p.Arg351Pro Uncertain significance ★★ ⚠ same condition
BMP1 p.Arg395His Uncertain significance ★★ same condition
BMP1 p.Arg508His Uncertain significance ★★ ⚠ same condition
BMP1 p.Arg524Cys Uncertain significance ★★ ⚠ same condition
BMP1 p.Arg562Trp 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/bmp1-p-ser458arg (accessed [today's date]).

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