Is BMPR2 p.Thr112Lys (c.335C>A) pathogenic?

BMPR2 p.Thr112Lys (c.335C>A) is classified Uncertain significance in BMPR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-22). AlphaMissense: ambiguous (0.4651); Absent from gnomAD v4.1; Associated with Primary pulmonary hypertension.

What condition is associated with BMPR2 p.Thr112Lys (c.335C>A)?

BMPR2 p.Thr112Lys (c.335C>A) is associated with Primary pulmonary hypertension (ClinVar).

How common is BMPR2 p.Thr112Lys (c.335C>A) in the general population?

BMPR2 p.Thr112Lys (c.335C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BMPR2 p.Thr112Lys (c.335C>A)?

AlphaMissense predicts ambiguous (score 0.4651) — an in-silico prediction, not a clinical call.

BMPR2 p.Thr112Lys

c.335C>A · rs2105962314 · VCV1056659

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4651 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,602,844)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Primary pulmonary hypertension

Computational evidence

Protein change
AlphaMissense	0.4651	ambiguous
REVEL	0.811	moderately pathogenic-leaning
SaProt	LLR -4.35	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense 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 0.78	unconstrained · MANE · 153 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	27.3	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

No allele count reported in gnomAD v4.1 (AN 1,602,844). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: BMPR2
Protein: p.Thr112Lys
Coding: c.335C>A
MANE Select: NM_001204
dbSNP: rs2105962314
Type: single nucleotide variant
Location: chr2:202467606 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.07 · 7 PDB
Residue 112: a disulfide bond

Full BMPR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Primary pulmonary hypertension — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BMPR2 p.Thr112Ala Uncertain significance ★ ⚠ same residue
BMPR2 c.1128+1G>A Pathogenic ★★ same condition
BMPR2 c.1128+1G>C Pathogenic ★★ same condition
BMPR2 c.621+1G>T Pathogenic/Likely pathogenic ★★ same condition
BMPR2 c.853-2A>G Pathogenic ★★ same condition
BMPR2 p.Arg147Ter Pathogenic ★★ same condition
BMPR2 p.Arg213Ter Pathogenic ★★ same condition
BMPR2 p.Arg491Trp 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/bmpr2-p-thr112lys (accessed [today's date]).

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