# NM_000942.5(PPIB):c.66C>A (p.Val22=)

https://sugi.bio/variant/ppib-p-val22

## Summary

**PPIB p.Val22= (c.66C>A)** is classified **Likely benign** in PPIB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-01). Absent from gnomAD v4.1.

**At a glance:** Likely benign · review: Single submitter · rsID rs918766896 · 1 submitter · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the PPIB gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PPIB](https://sugi.bio/atlas/gene/PPIB/) |
| Protein change (HGVS p.) | p.Val22= |
| Coding change (HGVS c.) | c.66C>A |
| MANE Select transcript | [NM_000942](https://www.ncbi.nlm.nih.gov/nuccore/NM_000942) |
| dbSNP | [rs918766896](https://www.ncbi.nlm.nih.gov/snp/rs918766896/) |
| Variant type | single nucleotide variant |
| Location | chr15:64162921-64162921 (GRCh38) |
| ClinVar | [VCV2040641](https://www.ncbi.nlm.nih.gov/clinvar/variation/2040641/) |

**All HGVS expressions:** `LRG_10:g.5235C>A`, `LRG_10t1:c.66C>A`, `NC_000015.10:g.64162921G>T`, `NC_000015.9:g.64455120G>T`, `NG_012979.1:g.5235C>A`, `NG_131210.1:g.643G>T`, `NG_131211.1:g.142G>T`, `NM_000942.5:c.66C>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.37) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 2.123, GERP 0.659, phastCons 0.994 — highly conserved position (PP3-type support)
- CADD: **PHRED 18.25**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.37**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.37**.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**PPIB** population constraint: LOEUF 1.104, pLI 0.00015871, missense-Z 0.45842; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 91.98, 83% of residues very-high.

**8 experimental structure(s)** (PDB): [1CYN](https://www.rcsb.org/structure/1CYN), [3ICH](https://www.rcsb.org/structure/3ICH), [3ICI](https://www.rcsb.org/structure/3ICI), [8K0F](https://www.rcsb.org/structure/8K0F), [8K0I](https://www.rcsb.org/structure/8K0I), [8K0M](https://www.rcsb.org/structure/8K0M).

## What this gene does {#gene-function}

*Describes the biological roles of PPIB (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** PPIB's established molecular role includes RNA binding. In Reactome, PPIB is annotated in disease pathway(s) including **SARS-CoV-1 activates/modulates innate immune responses**.

**Disease mechanism (Reactome):** PPIB loss or alteration is curated in [SARS-CoV-1 activates/modulates innate immune responses](https://reactome.org/content/detail/R-HSA-9692916).

### Pathways affected {#pathways}

PPIB participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [SARS-CoV-1 activates/modulates innate immune responses](https://reactome.org/content/detail/R-HSA-9692916) | curated |
| [Collagen biosynthesis and modifying enzymes](https://reactome.org/content/detail/R-HSA-1650814) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** RNA binding, peptidyl-prolyl cis-trans isomerase activity, RNA polymerase binding.

**Biological process:** protein folding, neutrophil chemotaxis, positive regulation of multicellular organism growth, host-mediated activation of viral process, host-mediated activation of viral genome replication, protein stabilization.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-09-01.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2022-09-01 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related PPIB variant pages (same residue, condition, or type): [PPIB c.344-1G>T](/variant/ppib-c-344-minus-1g-t), [PPIB c.-91A>C](/variant/ppib-c-minus-91a-c), [PPIB p.Ala15Thr](/variant/ppib-p-ala15thr), [PPIB p.Arg7Ser](/variant/ppib-p-arg7ser), [PPIB p.Asn75Ser](/variant/ppib-p-asn75ser), [PPIB p.Glu183Ala](/variant/ppib-p-glu183ala), [PPIB p.Gly39Trp](/variant/ppib-p-gly39trp), [PPIB p.Lys116Arg](/variant/ppib-p-lys116arg).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 2040641). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*