Is PPIB p.Ile199= (c.597C>T) pathogenic?

PPIB p.Ile199= (c.597C>T) is classified Conflicting classifications of pathogenicity in PPIB (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-25). Rare (popmax 0.165%, mid); Associated with osteogenesis imperfecta type 9.

What condition is associated with PPIB p.Ile199= (c.597C>T)?

PPIB p.Ile199= (c.597C>T) is associated with osteogenesis imperfecta type 9 (ClinVar).

How common is PPIB p.Ile199= (c.597C>T) in the general population?

PPIB p.Ile199= (c.597C>T) is rare (popmax 0.165%, mid) (gnomAD).

PPIB p.Ile199=

c.597C>T · rs369889089 · VCV316701

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.165%, mid)

Conditions

osteogenesis imperfecta type 9

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 -1.4	GERP -4
Overall
CADD	5.56	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.165% Middle Eastern · 10/6,062 alleles

Filtering AF 0.0895% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0681%

Overall 0.0115% 186/1,614,186 alleles · rare exomes 167/1,461,890 · genomes 19/152,296 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.165%	606
South Asian	0.0714%	1,401
Remaining individualsnot grpmax-eligible	0.0144%	6,946
Admixed American	0.0117%	8,575
European (non-Finnish)	0.0078%	12,826
Ashkenazi Jewishnot grpmax-eligible	0.00675%	14,804
African / African-American	0.00133%	75,044

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: PPIB
Protein: p.Ile199=
Coding: c.597C>T
MANE Select: NM_000942
dbSNP: rs369889089
Type: single nucleotide variant
Location: chr15:64156077 (GRCh38)
Gene constraint: LOEUF 1.104 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.98 · 8 PDB
Residue 199: the ppiase cyclophilin-type domain; a β-strand

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

Disease context

osteogenesis imperfecta type 9 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PPIB c.-91A>C Uncertain significance ★★ same condition
PPIB p.Asn75Ser Uncertain significance ★★ ⚠ same condition
PPIB p.Phe100Leu Uncertain significance ★★ ⚠ same condition
PPIB c.135+14C>T Likely benign ★★ same condition
PPIB c.249+19G>T Benign/Likely benign ★★ same condition
PPIB c.529-21G>A Benign ★★ same condition
PPIB p.Gly29Arg Benign/Likely benign ★★ same condition
PPIB p.Ile205= Likely benign ★★ 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/ppib-p-ile199 (accessed [today's date]).

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