# NM_001368809.2(AMPD2):c.537G>A (p.Pro179=)

https://sugi.bio/variant/ampd2-p-pro179

## Summary

**AMPD2 p.Pro179= (c.537G>A)** is classified **Likely benign** in AMPD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-09). Ultra-rare (popmax 0.033%, mid); Associated with pontocerebellar hypoplasia type 9.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs776483432 · 2 submitters · 2 linked conditions · ultra-rare (popmax 0.033%, mid)

## For patients & families {#patients}

This is a change in the AMPD2 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to pontocerebellar hypoplasia type 9.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017590/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [AMPD2](https://sugi.bio/atlas/gene/AMPD2/) |
| Protein change (HGVS p.) | p.Pro179= |
| Coding change (HGVS c.) | c.537G>A |
| MANE Select transcript | [NM_001368809](https://www.ncbi.nlm.nih.gov/nuccore/NM_001368809) |
| dbSNP | [rs776483432](https://www.ncbi.nlm.nih.gov/snp/rs776483432/) |
| Variant type | single nucleotide variant |
| Location | chr1:109626731-109626731 (GRCh38) |
| ClinVar | [VCV541842](https://www.ncbi.nlm.nih.gov/clinvar/variation/541842/) |

**All HGVS expressions:** `NC_000001.10:g.110169353G>A`, `NC_000001.11:g.109626731G>A`, `NG_034075.1:g.11919G>A`, `NM_001257360.1:c.699G>A`, `NM_001257361.2:c.345G>A`, `NM_001308170.1:c.474G>A`, `NM_001368809.2:c.537G>A`, `NM_004037.9:c.537G>A`, `NM_139156.4:c.456G>A`

## 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 -5.006, GERP -3.17 — fast-evolving / accelerated position
- CADD: **PHRED 1.172**. 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, Δ0.33 acceptor 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 **0.033%** (mid) · FAF95 0.00581% · FAF99 0.00242% · 2/6,068 in the highest group · 28/1,612,536 alleles overall — ultra-rare (popmax 0.033%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.033% | 3,034 |
| Remaining individuals (not grpmax-eligible) | 0.00481% | 20,797 |
| East Asian | 0.00446% | 22,436 |
| African / African-American | 0.00267% | 37,441 |
| South Asian | 0.0022% | 45,505 |
| Admixed American | 0.00167% | 59,816 |
| European (non-Finnish) | 0.00136% | 73,697 |

*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}

**AMPD2** population constraint: LOEUF 0.705, pLI 1.3901e-08, missense-Z 3.6393. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 81.28, 59% of residues very-high.

**5 experimental structure(s)** (PDB): [26XC](https://www.rcsb.org/structure/26XC), [4NO3](https://www.rcsb.org/structure/4NO3), [4NO5](https://www.rcsb.org/structure/4NO5), [8HU6](https://www.rcsb.org/structure/8HU6), [8HUB](https://www.rcsb.org/structure/8HUB).

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

*Describes the biological roles of AMPD2 (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:** AMPD2's established molecular role includes AMP deaminase activity.


### Pathways affected {#pathways}

AMPD2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Purine salvage](https://reactome.org/content/detail/R-HSA-74217) | curated |

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

**Molecular function:** AMP deaminase activity, identical protein binding.

**Biological process:** IMP biosynthetic process, GMP salvage, cyclic purine nucleotide metabolic process, energy homeostasis.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-09-09.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-09 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |

## Associated conditions {#conditions}

[pontocerebellar hypoplasia type 9](https://sugi.bio/atlas/disease/pontocerebellar-hypoplasia-type-9/), [hereditary spastic paraplegia 63](https://sugi.bio/atlas/disease/hereditary-spastic-paraplegia-63/).

**Reported phenotype names (ClinVar):** Pontocerebellar hypoplasia type 9, Hereditary spastic paraplegia 63, not provided, none provided, Spastic paraplegia 63, autosomal recessive.

## Similar variants {#similar}

Related AMPD2 variant pages (same residue, condition, or type): [AMPD2 p.Pro179Leu](/variant/ampd2-p-pro179leu), [AMPD2 c.1698+1G>A](/variant/ampd2-c-1698-plus-1g-a), [AMPD2 p.Arg353Ter](/variant/ampd2-p-arg353ter), [AMPD2 p.Arg449Ter](/variant/ampd2-p-arg449ter), [AMPD2 p.Arg620His](/variant/ampd2-p-arg620his), [AMPD2 p.Arg789His](/variant/ampd2-p-arg789his), [AMPD2 p.Glu174Ter](/variant/ampd2-p-glu174ter), [AMPD2 c.1080+3G>A](/variant/ampd2-c-1080-plus-3g-a).

### 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 541842). 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.*