Is BPNT2 p.Leu112= (c.336G>A) pathogenic?

BPNT2 p.Leu112= (c.336G>A) is classified Conflicting classifications of pathogenicity in BPNT2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-18). Ultra-rare (popmax 0.0218%, nfe); Associated with chondrodysplasia with joint dislocations, gPAPP type.

What condition is associated with BPNT2 p.Leu112= (c.336G>A)?

BPNT2 p.Leu112= (c.336G>A) is associated with chondrodysplasia with joint dislocations, gPAPP type (ClinVar).

How common is BPNT2 p.Leu112= (c.336G>A) in the general population?

BPNT2 p.Leu112= (c.336G>A) is ultra-rare (popmax 0.0218%, nfe) (gnomAD).

BPNT2 p.Leu112=

c.336G>A · rs148820865 · VCV363409

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0218%, nfe)

Conditions

chondrodysplasia with joint dislocations, gPAPP type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.5	GERP 0.46, phastCons 1
Overall
CADD	12.7	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0218% European (non-Finnish) · 257/1,179,862 alleles

Filtering AF 0.0196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0187%

Overall 0.0164% 264/1,608,538 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0218%	4,591
Remaining individualsnot grpmax-eligible	0.00961%	10,403
African / African-American	0.00133%	74,936

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: BPNT2
Protein: p.Leu112=
Coding: c.336G>A
MANE Select: NM_017813
dbSNP: rs148820865
Type: single nucleotide variant
Location: chr8:56993250 (GRCh38)
Gene constraint: LOEUF 0.619 · pLI 0.79 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.55

Full BPNT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

chondrodysplasia with joint dislocations, gPAPP type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BPNT2 p.Arg187Ter Pathogenic ★★ same condition
BPNT2 c.-155C>G Uncertain significance ★★ same condition
BPNT2 c.*4264G>A Uncertain significance ★★ same condition
BPNT2 c.*5193A>G Uncertain significance ★★ same condition
BPNT2 p.Ala218Ser Uncertain significance ★★ ⚠ same condition
BPNT2 p.Arg187Gln Uncertain significance ★★ ⚠ same condition
BPNT2 p.Gly330Ser Uncertain significance ★★ ⚠ same condition
BPNT2 p.Lys235Arg Uncertain significance ★★ ⚠ 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/bpnt2-p-leu112 (accessed [today's date]).

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