# NM_000036.3(AMPD1):c.5del (p.Pro2fs)

https://sugi.bio/variant/ampd1-p-pro2fs

## Summary

**AMPD1 p.Pro2fs (c.5del)** is classified **Conflicting classifications of pathogenicity** in AMPD1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-26). Rare (popmax 0.778%, sas); Associated with myopathy due to myoadenylate deaminase deficiency.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs557878856 · 2 submitters · 1 linked condition · rare (popmax 0.778%, sas)

## For patients & families {#patients}

This is a change in the AMPD1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to myopathy due to myoadenylate deaminase deficiency.

*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/0015248/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [AMPD1](https://sugi.bio/atlas/gene/AMPD1/) |
| Protein change (HGVS p.) | p.Pro2fs |
| Coding change (HGVS c.) | c.5del |
| MANE Select transcript | [NM_000036](https://www.ncbi.nlm.nih.gov/nuccore/NM_000036) |
| dbSNP | [rs557878856](https://www.ncbi.nlm.nih.gov/snp/rs557878856/) |
| Variant type | Deletion |
| Location | chr1:114695467-114695467 (GRCh38) |
| ClinVar | [VCV779692](https://www.ncbi.nlm.nih.gov/clinvar/variation/779692/) |

**All HGVS expressions:** `NC_000001.10:g.115238089del`, `NC_000001.11:g.114695468del`, `NG_008012.1:g.5089del`, `NM_000036.2:c.104del`, `NM_000036.2:c.104delC`, `NM_000036.3:c.5del`, `NM_001172626.2:c.5del`

## 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 4.392, GERP 0.924, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.036, pLI 7.1588e-21. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 1 of 16**, so the transcript is predicted to undergo NMD.
- 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.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.778%** (sas) · FAF95 0.731% · FAF99 0.712% · 709/91,076 in the highest group · 738/1,613,870 alleles overall — rare (popmax 0.778%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.778% | 128 |
| Remaining individuals (not grpmax-eligible) | 0.032% | 3,125 |
| European (non-Finnish) | 0.000763% | 131,110 |

*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}

**AMPD1** population constraint: LOEUF 1.036, pLI 7.1588e-21, missense-Z 1.0985. *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 86.84, 73% of residues very-high.

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

*Describes the biological roles of AMPD1 (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:** AMPD1's established molecular role includes AMP deaminase activity.


### Pathways affected {#pathways}

AMPD1 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:** GMP salvage.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-26.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Benign).

**Submission history:** 2 submissions (2021–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Revvity Omics, Revvity | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-06-29 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-26 |

## Associated conditions {#conditions}

[myopathy due to myoadenylate deaminase deficiency](https://sugi.bio/atlas/disease/myopathy-due-to-myoadenylate-deaminase-deficiency/).

**Reported phenotype names (ClinVar):** Muscle AMP deaminase deficiency, Myoadenylate deaminase deficiency, myopathy due to, Adenosine monophosphate deaminase 1 deficiency, AMP deaminase 1 deficiency, Adenosine Monophosphate Deaminase 1, ADENOSINE MONOPHOSPHATE DEAMINASE-1 DEFICIENCY, MYOPATHY DUE TO, AMPD1 DEFICIENCY.

## Similar variants {#similar}

Related AMPD1 variant pages (same residue, condition, or type): [AMPD1 p.Pro2Ser](/variant/ampd1-p-pro2ser), [AMPD1 c.382-6del](/variant/ampd1-c-382-minus-6del), [AMPD1 p.Phe41fs](/variant/ampd1-p-phe41fs), [AMPD1 c.216-2del](/variant/ampd1-c-216-minus-2del), [AMPD1 c.35-7_35-4del](/variant/ampd1-c-35-minus-7-35-minus-4del), [AMPD1 c.548-3_548-2del](/variant/ampd1-c-548-minus-3-548-minus-2del), [AMPD1 c.767+3_767+6del](/variant/ampd1-c-767-plus-3-767-plus-6del), [AMPD1 p.Gly78fs](/variant/ampd1-p-gly78fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 779692). 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.*