Is PPIB p.Phe100Leu (c.300C>A) pathogenic?

PPIB p.Phe100Leu (c.300C>A) is classified Uncertain significance in PPIB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-23). AlphaMissense: likely pathogenic (0.9998); Very rare (popmax 0.000508%, nfe); Associated with osteogenesis imperfecta type 9.

What condition is associated with PPIB p.Phe100Leu (c.300C>A)?

PPIB p.Phe100Leu (c.300C>A) is associated with osteogenesis imperfecta type 9, osteogenesis imperfecta (ClinVar).

How common is PPIB p.Phe100Leu (c.300C>A) in the general population?

PPIB p.Phe100Leu (c.300C>A) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about PPIB p.Phe100Leu (c.300C>A)?

AlphaMissense predicts likely pathogenic (score 0.9998) — an in-silico prediction, not a clinical call.

PPIB p.Phe100Leu

c.300C>A · rs1420928651 · VCV887219

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9998 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

osteogenesis imperfecta type 9

Computational evidence

Protein change
AlphaMissense	0.9998	likely pathogenic · top 1% in PPIB
REVEL	0.442	indeterminate
SaProt	LLR -11.63	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 2.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 6,960 bp · p 0.77 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000508% European (non-Finnish) · 6/1,179,996 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,614,176 alleles · very rare exomes 6/1,461,860 · genomes 0/152,316 · 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.Phe100Leu
Coding: c.300C>A
MANE Select: NM_000942
dbSNP: rs1420928651
Type: single nucleotide variant
Location: chr15:64160147 (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 100: the ppiase cyclophilin-type domain; a turn

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

Also linked: osteogenesis imperfecta

Similar variants

PPIB c.-91A>C Uncertain significance ★★ same condition
PPIB p.Asn75Ser 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
PPIB p.Ser21= 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-phe100leu (accessed [today's date]).

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