# NM_024664.4(PPCS):c.309C>A (p.Ser103=)

https://sugi.bio/variant/ppcs-p-ser103

## Summary

**PPCS p.Ser103= (c.309C>A)** is classified **Benign** in PPCS (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-03). Common (popmax 5.19%, afr) — too common for a highly-penetrant pathogenic allele.

**At a glance:** Benign · review: Multiple submitters · rsID rs7524895 · 5 submitters · common (popmax 5.19%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the PPCS gene that is classified as benign — not considered disease-causing, submitted by 5 submitters.

*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 | [PPCS](https://sugi.bio/atlas/gene/PPCS/) |
| Protein change (HGVS p.) | p.Ser103= |
| Coding change (HGVS c.) | c.309C>A |
| MANE Select transcript | [NM_024664](https://www.ncbi.nlm.nih.gov/nuccore/NM_024664) |
| dbSNP | [rs7524895](https://www.ncbi.nlm.nih.gov/snp/rs7524895/) |
| Variant type | single nucleotide variant |
| Location | chr1:42456874-42456874 (GRCh38) |
| ClinVar | [VCV1566758](https://www.ncbi.nlm.nih.gov/clinvar/variation/1566758/) |

**All HGVS expressions:** `NC_000001.10:g.42922545C>A`, `NC_000001.11:g.42456874C>A`, `NG_163396.1:g.201C>A`, `NM_001077447.3:c.-12+246C>A`, `NM_001287506.1:c.-11-373C>A`, `NM_001287507.1:c.-327-373C>A`, `NM_001287508.2:c.-12+150C>A`, `NM_001287509.2:c.-12+291C>A`, `NM_001287510.2:c.-384C>A`, `NM_001287511.2:c.309C>A`, `NM_001355226.2:c.-983-373C>A`, `NM_024664.4:c.309C>A`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 5.19%, afr) — 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 (below), not from a missing predictor score.
- Conservation: phyloP -0.853, GERP -4.26 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 2.497**. 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: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **5.19%** (afr) · FAF95 5.06% · FAF99 5% · 3,897/75,068 in the highest group · 4,261/1,613,328 alleles overall — common (popmax 5.19%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 5.19% | 19 |
| Remaining individuals (not grpmax-eligible) | 0.28% | 357 |
| Admixed American | 0.24% | 417 |
| Middle Eastern | 0.132% | 758 |
| South Asian | 0.00878% | 11,386 |
| European (non-Finnish) | 0.00246% | 40,691 |

*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.*

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-03.

**Submitter consensus:** unanimous (5/5 Benign).

**Submission history:** 5 submissions (2019–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2019-02-22 |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Benign | criteria provided, single submitter | clinical testing | 2025-04-09 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2023-05-18 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-03 |

**Reported phenotype names (ClinVar):** not provided, PPCS-related disorder, not specified, none provided, PPCS-related condition, AllHighlyPenetrant.

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 1566758). 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.*