Is BPNT2 p.Leu90Phe (c.268C>T) pathogenic?

BPNT2 p.Leu90Phe (c.268C>T) is classified Uncertain significance in BPNT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: ambiguous (0.4817); Very rare (popmax 0.00549%, sas); Associated with chondrodysplasia with joint dislocations, gPAPP type.

What condition is associated with BPNT2 p.Leu90Phe (c.268C>T)?

BPNT2 p.Leu90Phe (c.268C>T) is associated with chondrodysplasia with joint dislocations, gPAPP type (ClinVar).

How common is BPNT2 p.Leu90Phe (c.268C>T) in the general population?

BPNT2 p.Leu90Phe (c.268C>T) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about BPNT2 p.Leu90Phe (c.268C>T)?

AlphaMissense predicts ambiguous (score 0.4817) — an in-silico prediction, not a clinical call.

BPNT2 p.Leu90Phe

c.268C>T · rs750573329 · VCV911596

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4817 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Conditions

chondrodysplasia with joint dislocations, gPAPP type

Computational evidence

Protein change
AlphaMissense	0.4817	ambiguous
REVEL	0.398	indeterminate
SaProt	LLR -8.61	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.3	GERP 1.3, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 30 kb · p 0.51 · regional, not allelic
Overall
CADD	29.0	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 0.00549% South Asian · 5/91,084 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000342% 5/1,459,862 alleles · very rare

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.Leu90Phe
Coding: c.268C>T
MANE Select: NM_017813
dbSNP: rs750573329
Type: single nucleotide variant
Location: chr8:56993318 (GRCh38)
Gene constraint: LOEUF 0.619 · pLI 0.79 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.55
Residue 90: the 'disordered' region

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-leu90phe (accessed [today's date]).

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