Is PPIB p.Arg95His (c.284G>A) pathogenic?

PPIB p.Arg95His (c.284G>A) is classified Uncertain significance in PPIB (ClinVar, Single submitter, 1 submitter; last evaluated 2018-11-01). AlphaMissense: likely pathogenic (0.9908); Very rare (popmax 0.00446%, eas); Associated with osteogenesis imperfecta.

What condition is associated with PPIB p.Arg95His (c.284G>A)?

PPIB p.Arg95His (c.284G>A) is associated with osteogenesis imperfecta (ClinVar).

How common is PPIB p.Arg95His (c.284G>A) in the general population?

PPIB p.Arg95His (c.284G>A) is very rare (popmax 0.00446%, eas) (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.Arg95His (c.284G>A)?

AlphaMissense predicts likely pathogenic (score 0.9908) — an in-silico prediction, not a clinical call.

PPIB p.Arg95His

c.284G>A · rs771584197 · VCV1702048

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9908 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

osteogenesis imperfecta

Computational evidence

Protein change
AlphaMissense	0.9908	likely pathogenic
REVEL	0.685	pathogenic-leaning
SaProt	LLR -14.19	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.1, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 6,960 bp · p 0.77 · regional, not allelic
Overall
CADD	33.0	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 0.00446% East Asian · 2/44,886 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00167% 27/1,614,096 alleles · very rare exomes 27/1,461,820 · genomes 0/152,276 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,443
South Asian	0.0022%	45,540
European (non-Finnish)	0.00186%	53,635
Remaining individualsnot grpmax-eligible	0.0016%	62,508

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.Arg95His
Coding: c.284G>A
MANE Select: NM_000942
dbSNP: rs771584197
Type: single nucleotide variant
Location: chr15:64160163 (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 95: 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 — 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.Arg95Cys Uncertain significance ★ ⚠ same residue
PPIB p.Arg95Ser Uncertain significance ★ ⚠ same residue
PPIB p.Arg95= Likely benign ★ same residue
PPIB p.Phe100Leu Uncertain significance ★★ ⚠ same condition
PPIB p.Thr108= Benign ★★ same condition
PPIB p.His166Pro Likely pathogenic ★ same condition
PPIB p.Met9Lys Likely pathogenic ★ ⚠ same condition
PPIB c.-8G>C 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/ppib-p-arg95his (accessed [today's date]).

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