Is PPIB p.Lys45Arg (c.134A>G) pathogenic?

PPIB p.Lys45Arg (c.134A>G) is classified Uncertain significance in PPIB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-30). AlphaMissense: likely benign (0.1909); Very rare (popmax 0.00401%, afr); Associated with Inborn genetic diseases.

What condition is associated with PPIB p.Lys45Arg (c.134A>G)?

PPIB p.Lys45Arg (c.134A>G) is associated with Inborn genetic diseases (ClinVar).

How common is PPIB p.Lys45Arg (c.134A>G) in the general population?

PPIB p.Lys45Arg (c.134A>G) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about PPIB p.Lys45Arg (c.134A>G)?

AlphaMissense predicts likely benign (score 0.1909) — an in-silico prediction, not a clinical call.

PPIB p.Lys45Arg

c.134A>G · rs962538470 · VCV2261839

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1909 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1909	likely benign
REVEL	0.243	benign-leaning
SaProt	LLR -9.40	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.43	donor loss, 1 bp away · masked 0 · deltas
Pangolin	Δ0.64	loss · gain 0.25 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 6,960 bp · p 0.77 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00401% African / African-American · 3/74,872 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.00106% 17/1,610,822 alleles · very rare exomes 16/1,458,640 · genomes 1/152,182 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,957
Remaining individualsnot grpmax-eligible	0.0016%	62,306
European (non-Finnish)	0.0011%	90,688

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.Lys45Arg
Coding: c.134A>G
MANE Select: NM_000942
dbSNP: rs962538470
Type: single nucleotide variant
Location: chr15:64162853 (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 45: a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PPIB p.Arg7Ser Uncertain significance ★★ ⚠ same condition
PPIB p.Asn75Ser Uncertain significance ★★ ⚠ same condition
PPIB p.Glu183Ala Uncertain significance ★★ ⚠ same condition
PPIB p.Gly39Trp Uncertain significance ★★ ⚠ same condition
PPIB p.Lys116Arg Uncertain significance ★★ ⚠ same condition
PPIB p.Lys92Arg Uncertain significance ★★ ⚠ same condition
PPIB p.Thr113Ile Uncertain significance ★★ ⚠ same condition
PPIB p.Tyr88Cys 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-lys45arg (accessed [today's date]).

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