# NM_176869.3(PPA2):c.513C>T (p.Cys171=)

https://sugi.bio/variant/ppa2-p-cys171

## Summary

**PPA2 p.Cys171= (c.513C>T)** is classified **Benign/Likely benign** in PPA2 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-06-01). Rare (popmax 0.446%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs138826533 · 10 submitters · 1 linked condition · rare (popmax 0.446%, nfe)

## For patients & families {#patients}

This is a change in the PPA2 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 10 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 | [PPA2](https://sugi.bio/atlas/gene/PPA2/) |
| Protein change (HGVS p.) | p.Cys171= |
| Coding change (HGVS c.) | c.513C>T |
| MANE Select transcript | [NM_176869](https://www.ncbi.nlm.nih.gov/nuccore/NM_176869) |
| dbSNP | [rs138826533](https://www.ncbi.nlm.nih.gov/snp/rs138826533/) |
| Variant type | single nucleotide variant |
| Location | chr4:105437965-105437965 (GRCh38) |
| ClinVar | [VCV773156](https://www.ncbi.nlm.nih.gov/clinvar/variation/773156/) |

**All HGVS expressions:** `NC_000004.11:g.106359122G>A`, `NC_000004.12:g.105437965G>A`, `NG_053007.1:g.41106C>T`, `NM_006903.4:c.441+8418C>T`, `NM_176866.2:c.223-13643C>T`, `NM_176867.3:c.157+35929C>T`, `NM_176869.3:c.513C>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 1.586, GERP -0.827, phastCons 0.999 — weakly conserved position
- CADD: **PHRED 10.18**. 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 (G>T, Δ0.25 donor loss), 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 **0.446%** (nfe) · FAF95 0.436% · FAF99 0.431% · 5,247/1,177,140 in the highest group · 5,951/1,604,906 alleles overall — rare (popmax 0.446%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.738% | 135 |
| European (non-Finnish) (grpmax) | 0.446% | 224 |
| Middle Eastern | 0.333% | 301 |
| Remaining individuals (not grpmax-eligible) | 0.315% | 317 |
| South Asian | 0.126% | 793 |
| Admixed American | 0.121% | 829 |
| African / African-American | 0.0713% | 1,402 |
| Finnish (not grpmax-eligible) | 0.0581% | 1,721 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**PPA2** population constraint: LOEUF 1.324, pLI 1.4061e-09, missense-Z -0.42341. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **dilated cardiomyopathy** — Strong (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 87.39, 79% of residues very-high.

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

*Describes the biological roles of PPA2 (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:** PPA2's established molecular role includes inorganic diphosphate phosphatase activity.


### Pathways affected {#pathways}

PPA2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Mitochondrial tRNA aminoacylation](https://reactome.org/content/detail/R-HSA-379726) | other |
| [Pyrophosphate hydrolysis](https://reactome.org/content/detail/R-HSA-71737) | other |

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

**Molecular function:** inorganic diphosphate phosphatase activity.

**Biological process:** regulation of mitochondrial membrane potential, diphosphate metabolic process.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-06-01.

**Submitter consensus:** conflicting (7 Likely benign, 3 Benign).

**Submission history:** 10 submissions (2021–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2021-02-26 |
| Clinical Genetics, Academic Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-05-15 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| 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 | Benign | criteria provided, single submitter | clinical testing | 2025-03-19 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-01 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-06-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-18 |

## 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, none provided, AllHighlyPenetrant.

## Similar variants {#similar}

Related PPA2 variant pages (same residue, condition, or type): [PPA2 p.Ala12Val](/variant/ppa2-p-ala12val), [PPA2 p.Ala16Val](/variant/ppa2-p-ala16val), [PPA2 p.Arg9Leu](/variant/ppa2-p-arg9leu), [PPA2 p.Asn260Ser](/variant/ppa2-p-asn260ser), [PPA2 p.Asn319Tyr](/variant/ppa2-p-asn319tyr), [PPA2 p.Asp156Tyr](/variant/ppa2-p-asp156tyr), [PPA2 p.Asp245Asn](/variant/ppa2-p-asp245asn), [PPA2 p.Gln251Leu](/variant/ppa2-p-gln251leu).

### 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 773156). 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.*