# NM_001368809.2(AMPD2):c.1275G>A (p.Ala425=)

https://sugi.bio/variant/ampd2-p-ala425

## Summary

**AMPD2 p.Ala425= (c.1275G>A)** is classified **Uncertain significance** in AMPD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-07-03). Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs775359243 · 2 submitters · 3 linked conditions · very rare (popmax 0.00333%, amr)

## For patients & families {#patients}

This is a change in the AMPD2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 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 | [AMPD2](https://sugi.bio/atlas/gene/AMPD2/) |
| Protein change (HGVS p.) | p.Ala425= |
| Coding change (HGVS c.) | c.1275G>A |
| MANE Select transcript | [NM_001368809](https://www.ncbi.nlm.nih.gov/nuccore/NM_001368809) |
| dbSNP | [rs775359243](https://www.ncbi.nlm.nih.gov/snp/rs775359243/) |
| Variant type | single nucleotide variant |
| Location | chr1:109628277-109628277 (GRCh38) |
| ClinVar | [VCV2227783](https://www.ncbi.nlm.nih.gov/clinvar/variation/2227783/) |

**All HGVS expressions:** `NC_000001.10:g.110170899G>A`, `NC_000001.11:g.109628277G>A`, `NG_034075.1:g.13465G>A`, `NG_082146.2:g.738G>A`, `NM_001257360.2:c.1437G>A`, `NM_001257361.2:c.1083G>A`, `NM_001308170.1:c.1212G>A`, `NM_001368809.2:c.1275G>A`, `NM_004037.9:c.1275G>A`, `NM_139156.4:c.1194G>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.78) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 1.314, GERP 0.758, phastCons 1 — weakly conserved position
- CADD: **PHRED 21.7**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.78**, acceptor gain **0.00**, donor gain **0.09**. Largest is donor loss at this position.
  These are **raw** scores. Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — can legitimately show 0 where this shows a score; the masked figures are not available for this record.
- Pangolin: Δ**0.68** (loss), gain 0.02 / loss 0.68. 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 **0.00333%** (amr) · FAF95 0.000553% · FAF99 0.000207% · 2/60,012 in the highest group · 3/1,460,672 alleles overall — very rare (popmax 0.00333%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00333% | 30,006 |
| European (non-Finnish) | 8.48e-05% | 1,179,188 |

*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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-07-03.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2021–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-10-12 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-07-03 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Hereditary spastic paraplegia 63, Pontocerebellar hypoplasia type 9, Spastic paraplegia 63, autosomal recessive.

## Similar variants {#similar}

Related AMPD2 variant pages (same residue, condition, or type): [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), [AMPD2 c.353+3G>A](/variant/ampd2-c-353-plus-3g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 2227783). 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.*