Is BMPR1A p.Pro2Leu (c.5C>T) pathogenic?

BMPR1A p.Pro2Leu (c.5C>T) is classified Conflicting classifications of pathogenicity in BMPR1A (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2024-12-16). AlphaMissense: likely benign (0.1012); Very rare (popmax 0.00538%, afr); Associated with juvenile polyposis syndrome.

What condition is associated with BMPR1A p.Pro2Leu (c.5C>T)?

BMPR1A p.Pro2Leu (c.5C>T) is associated with juvenile polyposis syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BMPR1A p.Pro2Leu (c.5C>T) in the general population?

BMPR1A p.Pro2Leu (c.5C>T) is very rare (popmax 0.00538%, afr) (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.Pro2Leu (c.5C>T)?

AlphaMissense predicts likely benign (score 0.1012) — an in-silico prediction, not a clinical call.

BMPR1A p.Pro2Leu

c.5C>T · rs143248687 · VCV182062

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.1012 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00538%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

juvenile polyposis syndrome

Computational evidence

Protein change
AlphaMissense	0.1012	likely benign
REVEL	0.24	benign-leaning
SaProt	LLR -5.93	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 3.2	GERP 1.5, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 14 kb · p 0.1 · regional, not allelic
Overall
CADD	19.96	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 0.00538% African / African-American · 4/74,418 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00131%

Overall 0.00205% 33/1,608,210 alleles · very rare exomes 32/1,456,026 · genomes 1/152,184 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00538%	18,605
Remaining individualsnot grpmax-eligible	0.00321%	31,126
European (non-Finnish)	0.00221%	45,216
Admixed American	0.00167%	60,000

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.Pro2Leu
Coding: c.5C>T
MANE Select: NM_004329
dbSNP: rs143248687
Type: single nucleotide variant
Location: chr10:86876023 (GRCh38)
Gene constraint: LOEUF 0.195 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 82.86 · 11 PDB
Residue 2: a UniProt-annotated variant site (in)

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: 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.Pro2Arg Uncertain significance ★★ ⚠ same residue
BMPR1A p.Pro2Ser Uncertain significance ★★ ⚠ same residue
BMPR1A p.Pro2Thr Benign/Likely benign ★★ same residue
BMPR1A p.Pro2delinsThrGlnLeuTyrIleTyrIleArgSerPheThrArgLysSerHisTer 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-pro2leu (accessed [today's date]).

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