# NM_176869.3(PPA2):c.731C>G (p.Pro244Arg)

https://sugi.bio/variant/ppa2-p-pro244arg

## Summary

**PPA2 p.Pro244Arg (c.731C>G)** is classified **Uncertain significance** in PPA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-27). AlphaMissense: ambiguous (0.4246); Very rare (popmax 0.00803%, afr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs375637385 · 1 submitter · AlphaMissense ambiguous · very rare (popmax 0.00803%, afr)

## For patients & families {#patients}

This is a change in the PPA2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [PPA2](https://sugi.bio/atlas/gene/PPA2/) |
| Protein change (HGVS p.) | p.Pro244Arg |
| Coding change (HGVS c.) | c.731C>G |
| MANE Select transcript | [NM_176869](https://www.ncbi.nlm.nih.gov/nuccore/NM_176869) |
| dbSNP | [rs375637385](https://www.ncbi.nlm.nih.gov/snp/rs375637385/) |
| Variant type | single nucleotide variant |
| Location | chr4:105399089-105399089 (GRCh38) |
| ClinVar | [VCV1395122](https://www.ncbi.nlm.nih.gov/clinvar/variation/1395122/) |

**All HGVS expressions:** `NC_000004.11:g.106320246G>C`, `NC_000004.12:g.105399089G>C`, `NG_053007.1:g.79982C>G`, `NM_006903.4:c.644C>G`, `NM_176866.2:c.425C>G`, `NM_176867.3:c.233C>G`, `NM_176869.3:c.731C>G`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this damaging; AlphaMissense is indeterminate — descriptive only.

- AlphaMissense **ambiguous** (0.4246) — no call either way
- REVEL 0.907 (moderately pathogenic-leaning)
- SaProt LLR -16.019 (damaging)
- → **In-silico consensus:** REVEL and SaProt both call this damaging; AlphaMissense is indeterminate
- SpliceAI predicts **donor gain** (Δ 0.66) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.792, GERP 1.9, phastCons 1 — highly conserved
- CADD: **PHRED 35.0**. 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 1.05** across the covering region of the MANE Select transcript (105,369,728–105,474,050), spanning 104,322 bp. Chi-square p 0.35. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.66**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.66**.
- Pangolin: Δ**0.52** (gain), gain 0.52 / loss 0.00. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00803%** (afr) · FAF95 0.00348% · FAF99 0.00229% · 6/74,722 in the highest group · 7/1,610,306 alleles overall — very rare (popmax 0.00803%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00803% | 12,454 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,396 |

*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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-06-27.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-06-27 |

**Reported phenotype names (ClinVar):** not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## Similar variants {#similar}

Related PPA2 variant pages (same residue, condition, or type): [PPA2 p.Arg127Leu](/variant/ppa2-p-arg127leu), [PPA2 p.Glu172Lys](/variant/ppa2-p-glu172lys), [PPA2 p.Pro228Leu](/variant/ppa2-p-pro228leu), [PPA2 p.Thr159Met](/variant/ppa2-p-thr159met), [PPA2 c.528+1G>T](/variant/ppa2-c-528-plus-1g-t), [PPA2 p.Ala12Val](/variant/ppa2-p-ala12val), [PPA2 p.Ala130Val](/variant/ppa2-p-ala130val), [PPA2 p.Ala16Val](/variant/ppa2-p-ala16val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1395122). 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.*