Is PPIB p.His166Pro (c.497A>C) pathogenic?

PPIB p.His166Pro (c.497A>C) is classified Likely pathogenic in PPIB (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-27). AlphaMissense: likely pathogenic (0.9941); Very rare (popmax 0.000339%, nfe); Associated with osteogenesis imperfecta.

What condition is associated with PPIB p.His166Pro (c.497A>C)?

PPIB p.His166Pro (c.497A>C) is associated with osteogenesis imperfecta (ClinVar).

How common is PPIB p.His166Pro (c.497A>C) in the general population?

PPIB p.His166Pro (c.497A>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

How is Osteogenesis imperfecta inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PPIB p.His166Pro (c.497A>C)?

AlphaMissense predicts likely pathogenic (score 0.9941) — an in-silico prediction, not a clinical call.

PPIB p.His166Pro

c.497A>C · VCV4689501

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9941 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

osteogenesis imperfecta

Computational evidence

Protein change
AlphaMissense	0.9941	likely pathogenic ✓ concordant with ClinVar
REVEL	0.792	moderately pathogenic-leaning
SaProt	LLR -13.89	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.8	GERP 2.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 6,960 bp · p 0.77 · regional, not allelic
Overall
CADD	27.7	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 0.000339% European (non-Finnish) · 4/1,180,028 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,614,172 alleles · very rare exomes 4/1,461,894 · genomes 0/152,278 · joint denominator

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.His166Pro
Coding: c.497A>C
MANE Select: NM_000942
Type: single nucleotide variant
Location: chr15:64156756 (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 166: the ppiase cyclophilin-type domain

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

Disease context

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

For Osteogenesis imperfecta (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: All ages
Prevalence: 1-5 / 10 000 (Worldwide)

Similar variants

PPIB p.Phe100Leu Uncertain significance ★★ ⚠ same condition
PPIB p.Thr108= Benign ★★ same condition
PPIB p.Met9Lys Likely pathogenic ★ ⚠ same condition
PPIB c.-8G>C Uncertain significance ★ same condition
PPIB c.-9C>G Conflicting classifications of pathogenicity ★ same condition
PPIB p.Arg95His Uncertain significance ★ ⚠ same condition
PPIB p.Gly134_Pro135insGly Uncertain significance same condition
PPIB c.344-1G>T Pathogenic/Likely pathogenic ★★ same type

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-his166pro (accessed [today's date]).

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