Is PPIB p.Arg95Cys (c.283C>T) pathogenic?

PPIB p.Arg95Cys (c.283C>T) is classified Uncertain significance in PPIB (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-17). AlphaMissense: likely pathogenic (0.9943); Very rare (popmax 0.00133%, afr).

How common is PPIB p.Arg95Cys (c.283C>T) in the general population?

PPIB p.Arg95Cys (c.283C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about PPIB p.Arg95Cys (c.283C>T)?

AlphaMissense predicts likely pathogenic (score 0.9943) — an in-silico prediction, not a clinical call.

PPIB p.Arg95Cys

c.283C>T · VCV4804727

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9943 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9943	likely pathogenic
REVEL	0.691	pathogenic-leaning
SaProt	LLR -15.46	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 9.7	GERP 2.2, 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 0.00133% African / African-American · 1/74,914 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000744% 12/1,613,930 alleles · very rare exomes 10/1,461,788 · genomes 2/152,142 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,914
European (non-Finnish)	0.000932%	107,267

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.Arg95Cys
Coding: c.283C>T
MANE Select: NM_000942
Type: single nucleotide variant
Location: chr15:64160164 (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

Similar variants

PPIB p.Arg95His Uncertain significance ★ ⚠ same residue
PPIB p.Arg95Ser Uncertain significance ★ ⚠ same residue
PPIB p.Arg95= Likely benign ★ same residue
PPIB c.344-1G>T Pathogenic/Likely pathogenic ★★ same type
PPIB c.-91A>C Uncertain significance ★★ same type
PPIB p.Ala15Thr Uncertain significance ★★ ⚠ same type
PPIB p.Arg7Ser Uncertain significance ★★ ⚠ same type
PPIB p.Asn75Ser Uncertain significance ★★ ⚠ 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-arg95cys (accessed [today's date]).

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