# NM_000942.5(PPIB):c.63C>A (p.Ser21=)

https://sugi.bio/variant/ppib-p-ser21

## Summary

**PPIB p.Ser21= (c.63C>A)** is classified **Benign** in PPIB (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Common (popmax 18.9%, amr) — too common for a highly-penetrant pathogenic allele; Associated with osteogenesis imperfecta type 9.

**At a glance:** Benign · review: Multiple submitters · rsID rs4904 · 8 submitters · 1 linked condition · common (popmax 18.9%, amr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the PPIB gene that is classified as benign — not considered disease-causing, submitted by 8 submitters, and is linked to osteogenesis imperfecta type 9.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010619/index) · [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.Ser21= |
| Coding change (HGVS c.) | c.63C>A |
| MANE Select transcript | [NM_000942](https://www.ncbi.nlm.nih.gov/nuccore/NM_000942) |
| dbSNP | [rs4904](https://www.ncbi.nlm.nih.gov/snp/rs4904/) |
| Variant type | single nucleotide variant |
| Location | chr15:64162924-64162924 (GRCh38) |
| ClinVar | [VCV31849](https://www.ncbi.nlm.nih.gov/clinvar/variation/31849/) |

**All HGVS expressions:** `LRG_10:g.5232C>A`, `LRG_10t1:c.63C>A`, `NC_000015.10:g.64162924G>T`, `NC_000015.9:g.64455123G>T`, `NG_012979.1:g.5232C>A`, `NM_000942.5:c.63C>A`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 18.9%, amr) — too common for a highly-penetrant pathogenic allele.

- **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 0.45) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.493, GERP -3.45, phastCons 0.002 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 17.61**. 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 **0.45**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.45**.
- Population frequency (gnomAD v4.1): grpmax **18.9%** (amr) · FAF95 18.6% · FAF99 18.5% · 11,321/59,876 in the highest group · 45,375/1,613,344 alleles overall — common (popmax 18.9%, amr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 18.9% | 5 |
| Finnish (not grpmax-eligible) | 4.72% | 21 |
| East Asian | 3.48% | 29 |
| Remaining individuals (not grpmax-eligible) | 2.63% | 38 |
| African / African-American | 2.35% | 43 |
| Middle Eastern | 2.27% | 44 |
| South Asian | 2% | 50 |
| European (non-Finnish) | 2% | 50 |
| Ashkenazi Jewish (not grpmax-eligible) | 1.91% | 52 |

*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}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** conflicting (6 Benign, 1 not provided).

**Submission history:** 6 submissions (2011–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2022-04-26 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2016-05-09 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-27 |
| Osteogenesis Imperfecta Variant Database (PPIB) | not provided | no classification provided | curation | 2011-02-17 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |

## Associated conditions {#conditions}

[osteogenesis imperfecta type 9](https://sugi.bio/atlas/disease/osteogenesis-imperfecta-type-9/).

**Reported phenotype names (ClinVar):** Osteogenesis imperfecta type 9, not provided, not specified, Uveal melanoma, Colon adenocarcinoma, Colorectal cancer, Sarcoma, Clear cell carcinoma of kidney, Lymphoma, Thyroid cancer, nonmedullary, 1.

## Similar variants {#similar}

Related PPIB variant pages (same residue, condition, or type): [PPIB c.-91A>C](/variant/ppib-c-minus-91a-c), [PPIB p.Asn75Ser](/variant/ppib-p-asn75ser), [PPIB p.Phe100Leu](/variant/ppib-p-phe100leu), [PPIB c.135+14C>T](/variant/ppib-c-135-plus-14c-t), [PPIB c.249+19G>T](/variant/ppib-c-249-plus-19g-t), [PPIB c.529-21G>A](/variant/ppib-c-529-minus-21g-a), [PPIB p.Gly29Arg](/variant/ppib-p-gly29arg), [PPIB p.Ile205=](/variant/ppib-p-ile205).

### 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 31849). 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.*