# NM_024664.4(PPCS):c.397A>T (p.Arg133Trp)

https://sugi.bio/variant/ppcs-p-arg133trp

## Summary

**PPCS p.Arg133Trp (c.397A>T)** is classified **Conflicting classifications of pathogenicity** in PPCS (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-11). AlphaMissense: likely benign (0.0909); Ultra-rare (popmax 0.0743%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs199807362 · 4 submitters · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0743%, nfe)

> **Built without this gene's context.** ClinVar files this variant under an overlapping gene, so its own gene's record set does not contain it and this page is assembled from the variant alone. Gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up — absent from this page, not from the data.

## For patients & families {#patients}

This is a change in the PPCS gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, and is linked to Inborn genetic diseases.

*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.Arg133Trp |
| Coding change (HGVS c.) | c.397A>T |
| MANE Select transcript | [NM_024664](https://www.ncbi.nlm.nih.gov/nuccore/NM_024664) |
| dbSNP | [rs199807362](https://www.ncbi.nlm.nih.gov/snp/rs199807362/) |
| Variant type | single nucleotide variant |
| Location | chr1:42456962-42456962 (GRCh38) |
| ClinVar | [VCV1512518](https://www.ncbi.nlm.nih.gov/clinvar/variation/1512518/) |

**All HGVS expressions:** `NC_000001.10:g.42922633A>T`, `NC_000001.11:g.42456962A>T`, `NG_163396.1:g.289A>T`, `NM_001077447.3:c.-11-285A>T`, `NM_001287506.1:c.-11-285A>T`, `NM_001287507.1:c.-327-285A>T`, `NM_001287508.2:c.-12+238A>T`, `NM_001287509.2:c.-11-285A>T`, `NM_001287510.2:c.-296A>T`, `NM_001287511.2:c.397A>T`, `NM_001355226.2:c.-983-285A>T`, `NM_024664.4:c.397A>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0909)
- REVEL 0.194 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -11.751 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense and REVEL do not
- Conservation: phyloP 1.876, GERP -0.801, phastCons 0.993 — weakly conserved position
- CADD: **PHRED 22.0**. 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.*
- Regional missense constraint: **o/e 1.04** across the covering region of the MANE Select transcript (42,456,566–42,457,253), spanning 687 bp. Chi-square p 0.55. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **0.0743%** (nfe) · FAF95 0.0702% · FAF99 0.0685% · 877/1,179,962 in the highest group · 967/1,604,040 alleles overall — ultra-rare (popmax 0.0743%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0743% | 1,345 |
| Remaining individuals (not grpmax-eligible) | 0.0705% | 1,419 |
| Admixed American | 0.045% | 2,223 |
| Finnish (not grpmax-eligible) | 0.0167% | 6,001 |
| South Asian | 0.00659% | 15,181 |
| African / African-American | 0.00533% | 18,762 |

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-11.

**Submitter consensus:** conflicting (2 Uncertain significance, 2 Likely benign).

**Submission history:** 4 submissions (2021–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-09-01 |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Likely benign | criteria provided, single submitter | clinical testing | 2025-04-09 |
| Mayo Clinic Laboratories, Mayo Clinic | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-27 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-11 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not provided, not specified, AllHighlyPenetrant, none provided.

### 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 1512518). 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.*