# NM_001025389.2(AMPD3):c.1270G>A (p.Val424Ile)

https://sugi.bio/variant/ampd3-p-val424ile

## Summary

**AMPD3 p.Val424Ile (c.1270G>A)** is classified **Uncertain significance** in AMPD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-31). AlphaMissense: likely benign (0.2378); Ultra-rare (popmax 0.0133%, afr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0133%, afr)

## For patients & families {#patients}

This is a change in the AMPD3 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 | [AMPD3](https://sugi.bio/atlas/gene/AMPD3/) |
| Protein change (HGVS p.) | p.Val424Ile |
| Coding change (HGVS c.) | c.1270G>A |
| MANE Select transcript | [NM_001025389](https://www.ncbi.nlm.nih.gov/nuccore/NM_001025389) |
| Variant type | single nucleotide variant |
| Location | chr11:10495573-10495573 (GRCh38) |
| ClinVar | [VCV3536742](https://www.ncbi.nlm.nih.gov/clinvar/variation/3536742/) |

**All HGVS expressions:** `NC_000011.10:g.10495573G>A`, `NC_000011.9:g.10517120G>A`, `NG_012041.1:g.49897G>A`, `NM_000480.3:c.1297G>A`, `NM_001025389.2:c.1270G>A`, `NM_001025390.2:c.1291G>A`, `NM_001172430.1:c.1270G>A`, `NM_001172431.2:c.793G>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.2378)
- REVEL 0.583 (indeterminate)
- SaProt LLR -7.003 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 11.914, GERP 1.89, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 29.6**. 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 0.87** across the covering region of the MANE Select transcript (10,461,520–10,505,881), spanning 44,361 bp. Chi-square p 2.4e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.21 acceptor 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 **0.0133%** (afr) · FAF95 0.00722% · FAF99 0.00549% · 10/74,990 in the highest group · 10/1,612,816 alleles overall — ultra-rare (popmax 0.0133%, afr).

*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}

**AMPD3** population constraint: LOEUF 0.817, pLI 1.5297e-12, missense-Z 2.0819. *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 85.74, 68% of residues very-high.

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

*Describes the biological roles of AMPD3 (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.*


### Pathways affected {#pathways}

AMPD3 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Purine salvage](https://reactome.org/content/detail/R-HSA-74217) | curated |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-07-31.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-07-31 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related AMPD3 variant pages (same residue, condition, or type): [AMPD3 c.1135-5C>A](/variant/ampd3-c-1135-minus-5c-a), [AMPD3 c.1135-6C>G](/variant/ampd3-c-1135-minus-6c-g), [AMPD3 c.1267-3C>T](/variant/ampd3-c-1267-minus-3c-t), [AMPD3 c.*287T>C](/variant/ampd3-c-star-287t-c), [AMPD3 c.*75C>T](/variant/ampd3-c-star-75c-t), [AMPD3 p.Ala141=](/variant/ampd3-p-ala141), [AMPD3 p.Arg426Trp](/variant/ampd3-p-arg426trp), [AMPD3 p.Arg576=](/variant/ampd3-p-arg576).

### 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 3536742). 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.*