Is BMP5 p.Ile401Met (c.1203A>G) pathogenic?

BMP5 p.Ile401Met (c.1203A>G) is classified Uncertain significance in BMP5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-03). AlphaMissense: likely pathogenic (0.9663); Very rare (popmax 8.53e-05%, nfe).

How common is BMP5 p.Ile401Met (c.1203A>G) in the general population?

BMP5 p.Ile401Met (c.1203A>G) is very rare (popmax 8.53e-05%, nfe) (gnomAD).

What do computational predictors say about BMP5 p.Ile401Met (c.1203A>G)?

AlphaMissense predicts likely pathogenic (score 0.9663) — an in-silico prediction, not a clinical call.

BMP5 p.Ile401Met

c.1203A>G · rs2481606690 · VCV2322385

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9663 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.53e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9663	likely pathogenic
REVEL	0.653	pathogenic-leaning
SaProt	LLR -12.02	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.075	GERP -4.2, phastCons 0.97
Regional constraint	o/e 0.96	unconstrained · MANE · 119 kb · p 0.39 · regional, not allelic
Overall
CADD	21.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.53e-05% European (non-Finnish) · 1/1,172,348 alleles

Overall 6.88e-05% 1/1,453,666 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: BMP5
Protein: p.Ile401Met
Coding: c.1203A>G
MANE Select: NM_021073
dbSNP: rs2481606690
Type: single nucleotide variant
Location: chr6:55759017 (GRCh38)
Gene constraint: LOEUF 0.711 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.85
Residue 401: a disulfide bond

Full BMP5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BMP5 p.Ala103Thr Uncertain significance ★ ⚠ same type
BMP5 p.Ala118Asp Uncertain significance ★ ⚠ same type
BMP5 p.Ala25Thr Uncertain significance ★ ⚠ same type
BMP5 p.Ala307Glu Uncertain significance ★ ⚠ same type
BMP5 p.Ala317Val Uncertain significance ★ ⚠ same type
BMP5 p.Ala74Thr Uncertain significance ★ ⚠ same type
BMP5 p.Ala77Val Uncertain significance ★ ⚠ same type
BMP5 p.Arg125Cys 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/bmp5-p-ile401met (accessed [today's date]).

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