Is BMPR1A p.Pro140Ser (c.418C>T) pathogenic?

BMPR1A p.Pro140Ser (c.418C>T) is classified Uncertain significance in BMPR1A (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-12-15). AlphaMissense: likely benign (0.2176); Very rare (popmax 0.0011%, sas); Associated with juvenile polyposis syndrome.

What condition is associated with BMPR1A p.Pro140Ser (c.418C>T)?

BMPR1A p.Pro140Ser (c.418C>T) is associated with juvenile polyposis syndrome, polyposis syndrome, hereditary mixed, 2, hereditary neoplastic syndrome (ClinVar).

How common is BMPR1A p.Pro140Ser (c.418C>T) in the general population?

BMPR1A p.Pro140Ser (c.418C>T) is very rare (popmax 0.0011%, sas) (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.Pro140Ser (c.418C>T)?

AlphaMissense predicts likely benign (score 0.2176) — an in-silico prediction, not a clinical call.

BMPR1A p.Pro140Ser

c.418C>T · rs138478597 · VCV438903

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.2176 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

juvenile polyposis syndrome

Computational evidence

Protein change
AlphaMissense	0.2176	likely benign
REVEL	0.557	indeterminate
SaProt	LLR -12.45	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 27 kb · p 2.2e-08 · regional, not allelic
Overall
CADD	25.2	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 0.0011% South Asian · 1/91,084 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000496% 8/1,614,000 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,084
European (non-Finnish)	0.000593%	168,563

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.Pro140Ser
Coding: c.418C>T
MANE Select: NM_004329
dbSNP: rs138478597
Type: single nucleotide variant
Location: chr10:86899878 (GRCh38)
Gene constraint: LOEUF 0.195 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 82.86 · 11 PDB
Residue 140: an α-helix

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.Pro140Ala Uncertain significance ★★ ⚠ same residue
BMPR1A p.Pro140Leu Uncertain significance ★★ ⚠ same residue
BMPR1A p.Pro140Arg Uncertain significance ★ ⚠ same residue
BMPR1A p.Pro140fs Pathogenic ★★ 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-pro140ser (accessed [today's date]).

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