Is BMPR1A p.Pro2Thr (c.4C>A) pathogenic?

BMPR1A p.Pro2Thr (c.4C>A) is classified Benign/Likely benign in BMPR1A (ClinVar, Multiple submitters, 22 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0793); Common (popmax 71.6%, eas) — too common for a highly-penetrant pathogenic allele; Associated with juvenile polyposis syndrome.

What condition is associated with BMPR1A p.Pro2Thr (c.4C>A)?

BMPR1A p.Pro2Thr (c.4C>A) is associated with juvenile polyposis syndrome, generalized juvenile polyposis/juvenile polyposis coli, hereditary neoplastic syndrome (ClinVar).

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.Pro2Thr (c.4C>A)?

AlphaMissense predicts likely benign (score 0.0793) — an in-silico prediction, not a clinical call.

BMPR1A p.Pro2Thr

Q: How common is BMPR1A p.Pro2Thr (c.4C>A) in the general population?

BMPR1A p.Pro2Thr (c.4C>A) is common (popmax 71.6%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.4C>A · rs11528010 · VCV41782

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 22 submitters

AlphaMissense

likely benign

0.0793 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 71.6%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

juvenile polyposis syndrome

Computational evidence

Protein change
AlphaMissense	0.0793	likely benign
REVEL	0.206	benign-leaning
SaProt	LLR -5.99	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 7.8	GERP 1.3, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 14 kb · p 0.1 · regional, not allelic
Overall
CADD	14.97	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 71.6% East Asian · 31,934/44,614 alleles

Filtering AF 70.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 70.6%

Overall 29.7% 473,381/1,592,936 alleles · common exomes 411,907/1,440,912 · genomes 61,474/152,024 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	71.6%	1
African / African-American	66.8%	1
Ashkenazi Jewishnot grpmax-eligible	38.1%	3
Admixed American	37.6%	3
Finnishnot grpmax-eligible	36.4%	3
Middle Eastern	35.3%	3
Remaining individualsnot grpmax-eligible	32.4%	3
South Asian	30%	3
European (non-Finnish)	24.6%	4
Amishnot grpmax-eligible	24%	4

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.Pro2Thr
Coding: c.4C>A
MANE Select: NM_004329
dbSNP: rs11528010
Type: single nucleotide variant
Location: chr10:86876022 (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: generalized juvenile polyposis/juvenile polyposis coli 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.Pro2Leu Conflicting classifications of pathogenicity ★ ⚠ 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-pro2thr (accessed [today's date]).

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