# NM_024664.4(PPCS):c.402C>T (p.Ser134=)

https://sugi.bio/variant/ppcs-p-ser134

## Summary

**PPCS p.Ser134= (c.402C>T)** is classified **Likely benign** in PPCS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-04). Ultra-rare (popmax 0.034%, sas).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · ultra-rare (popmax 0.034%, sas)

## For patients & families {#patients}

This is a change in the PPCS 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 | [PPCS](https://sugi.bio/atlas/gene/PPCS/) |
| Protein change (HGVS p.) | p.Ser134= |
| Coding change (HGVS c.) | c.402C>T |
| MANE Select transcript | [NM_024664](https://www.ncbi.nlm.nih.gov/nuccore/NM_024664) |
| Variant type | single nucleotide variant |
| Location | chr1:42456967-42456967 (GRCh38) |
| ClinVar | [VCV3717826](https://www.ncbi.nlm.nih.gov/clinvar/variation/3717826/) |

**All HGVS expressions:** `NC_000001.10:g.42922638C>T`, `NC_000001.11:g.42456967C>T`, `NG_163396.1:g.294C>T`, `NM_001077447.3:c.-11-280C>T`, `NM_001287506.1:c.-11-280C>T`, `NM_001287507.1:c.-327-280C>T`, `NM_001287508.2:c.-12+243C>T`, `NM_001287509.2:c.-11-280C>T`, `NM_001287510.2:c.-291C>T`, `NM_001287511.2:c.402C>T`, `NM_001355226.2:c.-983-280C>T`, `NM_024664.4:c.402C>T`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 0.603, GERP 1.15, phastCons 0.998 — weakly conserved position
- CADD: **PHRED 7.57**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.31 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.034%** (sas) · FAF95 0.0246% · FAF99 0.0214% · 31/91,092 in the highest group · 31/1,604,082 alleles overall — ultra-rare (popmax 0.034%, sas).

*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}

**PPCS** population constraint: LOEUF 1.064, pLI 6.3481e-05, missense-Z 0.81988. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **134** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 93.94, 85% of residues very-high.

**2 experimental structure(s)** (PDB): [1P9O](https://www.rcsb.org/structure/1P9O), [7EDZ](https://www.rcsb.org/structure/7EDZ).

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

*Describes the biological roles of PPCS (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:** PPCS's established molecular role includes phosphopantothenate--cysteine ligase activity.


### Pathways affected {#pathways}

PPCS participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Coenzyme A biosynthesis](https://reactome.org/content/detail/R-HSA-196783) | curated |

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

**Molecular function:** phosphopantothenate--cysteine ligase activity, identical protein binding, protein homodimerization activity.

**Biological process:** heart process, acetyl-CoA biosynthetic process, coenzyme A biosynthetic process.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-06-04.

**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 | 2025-06-04 |

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

## Similar variants {#similar}

Related PPCS variant pages (same residue, condition, or type): [PPCS p.Ala162Pro](/variant/ppcs-p-ala162pro), [PPCS p.Pro107Ser](/variant/ppcs-p-pro107ser), [PPCS c.*91T>G](/variant/ppcs-c-star-91t-g), [PPCS p.Leu280=](/variant/ppcs-p-leu280), [PPCS p.Phe73=](/variant/ppcs-p-phe73), [PPCS p.Ala8Ser](/variant/ppcs-p-ala8ser), [PPCS p.Leu118Met](/variant/ppcs-p-leu118met), [PPCS p.Thr68Pro](/variant/ppcs-p-thr68pro).

### 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 3717826). 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.*