Is BMPR1A p.Pro397Ser (c.1189C>T) pathogenic?

BMPR1A p.Pro397Ser (c.1189C>T) is classified Uncertain significance in BMPR1A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-29). AlphaMissense: likely pathogenic (0.5718); Very rare (popmax 8.47e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BMPR1A p.Pro397Ser (c.1189C>T)?

BMPR1A p.Pro397Ser (c.1189C>T) is associated with hereditary neoplastic syndrome, juvenile polyposis syndrome (ClinVar).

How common is BMPR1A p.Pro397Ser (c.1189C>T) in the general population?

BMPR1A p.Pro397Ser (c.1189C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about BMPR1A p.Pro397Ser (c.1189C>T)?

AlphaMissense predicts likely pathogenic (score 0.5718) — an in-silico prediction, not a clinical call.

BMPR1A p.Pro397Ser

c.1189C>T · rs1843665120 · VCV927603

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.5718 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.5718	likely pathogenic
REVEL	0.253	benign-leaning
SaProt	LLR -8.26	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 6	GERP 0.93, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 4,412 bp · p 2.1e-15 · regional, not allelic
Overall
CADD	24.6	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 8.47e-05% European (non-Finnish) · 1/1,179,966 alleles

Overall 6.84e-05% 1/1,461,760 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: BMPR1A
Protein: p.Pro397Ser
Coding: c.1189C>T
MANE Select: NM_004329
dbSNP: rs1843665120
Type: single nucleotide variant
Location: chr10:86921542 (GRCh38)
Gene constraint: LOEUF 0.195 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 82.86 · 11 PDB
Residue 397: the protein kinase domain

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

Disease context

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

Also linked: juvenile polyposis syndrome

Similar variants

BMPR1A p.Pro397Leu Uncertain significance ★★ ⚠ same residue
BMPR1A p.Pro397= Benign/Likely benign ★★ same residue
BMPR1A p.Pro397_Leu398insTer Pathogenic ★ same residue
BMPR1A p.Pro397Arg Uncertain significance ★ ⚠ 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

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-pro397ser (accessed [today's date]).

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