Is BMPR1A p.Ile445Val (c.1333A>G) pathogenic?

BMPR1A p.Ile445Val (c.1333A>G) is classified Conflicting classifications of pathogenicity in BMPR1A (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-17). AlphaMissense: likely benign (0.0522); Ultra-rare (popmax 0.0164%, mid); Associated with juvenile polyposis syndrome.

What condition is associated with BMPR1A p.Ile445Val (c.1333A>G)?

BMPR1A p.Ile445Val (c.1333A>G) is associated with juvenile polyposis syndrome, polyposis syndrome, hereditary mixed, 2, hereditary neoplastic syndrome (ClinVar).

How common is BMPR1A p.Ile445Val (c.1333A>G) in the general population?

BMPR1A p.Ile445Val (c.1333A>G) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

How is Juvenile polyposis syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about BMPR1A p.Ile445Val (c.1333A>G)?

AlphaMissense predicts likely benign (score 0.0522) — an in-silico prediction, not a clinical call.

BMPR1A p.Ile445Val

c.1333A>G · rs587781503 · VCV141113

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0522 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

juvenile polyposis syndrome

Computational evidence

Protein change
AlphaMissense	0.0522	likely benign
REVEL	0.183	benign-leaning
SaProt	LLR -4.64	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.25	GERP -1.9
Regional constraint	o/e 0.51	unconstrained · MANE · 4,412 bp · p 2.1e-15 · regional, not allelic
Overall
CADD	6.489	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00062% 10/1,614,134 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Admixed American	0.00833%	12,002
African / African-American	0.004%	24,985
European (non-Finnish)	8.47e-05%	1,180,057

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: BMPR1A
Protein: p.Ile445Val
Coding: c.1333A>G
MANE Select: NM_004329
dbSNP: rs587781503
Type: single nucleotide variant
Location: chr10:86921686 (GRCh38)
Gene constraint: LOEUF 0.195 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 82.86 · 11 PDB
Residue 445: the protein kinase domain

Full BMPR1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

juvenile polyposis syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: polyposis syndrome, hereditary mixed, 2 hereditary neoplastic syndrome

For Juvenile polyposis syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

BMPR1A p.Ile445= Benign/Likely benign ★★ same residue
BMPR1A c.1166+1G>A Likely pathogenic ★★ same condition
BMPR1A c.1343-2A>G Likely pathogenic ★★ same condition
BMPR1A c.1473+1G>A Pathogenic/Likely pathogenic ★★ same condition
BMPR1A c.1473+1G>C Pathogenic/Likely pathogenic ★★ same condition
BMPR1A c.230+1G>A Likely pathogenic ★★ same condition
BMPR1A c.333+1G>A Likely pathogenic ★★ same condition
BMPR1A c.430+1G>A Pathogenic ★★ 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/bmpr1a-p-ile445val (accessed [today's date]).

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