# NM_001625.4(AK2):c.714dup (p.Ile239fs)

https://sugi.bio/variant/ak2-p-ile239fs

## Summary

**AK2 p.Ile239fs (c.714dup)** is classified **Uncertain significance** in AK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-02). No gnomAD frequency available for this variant; Associated with reticular dysgenesis.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2124278051 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the AK2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to reticular dysgenesis.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Prevalence | <1 / 1 000 000 (Europe) |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | AK2 is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of Reticular dysgenesis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hearing impairment — Very frequent (99-80%)
- Chronic otitis media — Very frequent (99-80%)
- Abnormality of neutrophils — Very frequent (99-80%)
- Leukopenia — Very frequent (99-80%)
- Anemia — Very frequent (99-80%)
- Diarrhea — Very frequent (99-80%)
- Recurrent respiratory infections — Very frequent (99-80%)
- Abnormality of mitochondrial metabolism — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0008625/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [AK2](https://sugi.bio/atlas/gene/AK2/) |
| Protein change (HGVS p.) | p.Ile239fs |
| Coding change (HGVS c.) | c.714dup |
| MANE Select transcript | [NM_001625](https://www.ncbi.nlm.nih.gov/nuccore/NM_001625) |
| dbSNP | [rs2124278051](https://www.ncbi.nlm.nih.gov/snp/rs2124278051/) |
| Variant type | Duplication |
| Location | chr1:33013186-33013187 (GRCh38) |
| ClinVar | [VCV1384263](https://www.ncbi.nlm.nih.gov/clinvar/variation/1384263/) |

**All HGVS expressions:** `LRG_133:g.28705dup`, `NC_000001.10:g.33478790dup`, `NC_000001.11:g.33013189dup`, `NG_016269.1:g.28705dup`, `NM_001199199.3:c.670+20dup`, `NM_001319139.3:c.550+20dup`, `NM_001319140.2:c.570dup`, `NM_001319141.3:c.694+20dup`, `NM_001319142.3:c.568+20dup`, `NM_001319143.2:c.*217dup`, `NM_001625.4:c.714dup`, `NM_013411.5:c.694+20dup`

## 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 4.184, GERP 2.73, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.954, pLI 0.00086478. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (6 of 6)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**AK2** population constraint: LOEUF 0.954, pLI 0.00086478, missense-Z 0.77091. *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):

- **reticular dysgenesis** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 90.49, 83% of residues very-high.

**3 experimental structure(s)** (PDB): [2C9Y](https://www.rcsb.org/structure/2C9Y), [9FL7](https://www.rcsb.org/structure/9FL7), [9GR0](https://www.rcsb.org/structure/9GR0).

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

*Describes the biological roles of AK2 (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:** AK2's established molecular role includes AMP kinase activity.


### Pathways affected {#pathways}

AK2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Interconversion of nucleotide di- and triphosphates](https://reactome.org/content/detail/R-HSA-499943) | curated |

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

**Molecular function:** AMP kinase activity.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-04-02.

**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 | 2021-04-02 |

## Associated conditions {#conditions}

[reticular dysgenesis](https://sugi.bio/atlas/disease/reticular-dysgenesis/).

**Reported phenotype names (ClinVar):** Reticular dysgenesis, ALEUKOCYTOSIS, CONGENITAL ALEUKIA, HEMATOPOIETIC HYPOPLASIA, GENERALIZED, RETICULAR DYSGENESIA, SEVERE COMBINED IMMUNODEFICIENCY WITH LEUKOPENIA, DeVaal disease.

## Similar variants {#similar}

Related AK2 variant pages (same residue, condition, or type): [AK2 p.Gly29fs](/variant/ak2-p-gly29fs), [AK2 c.220-2dup](/variant/ak2-c-220-minus-2dup), [AK2 p.Val236_Met237insIle](/variant/ak2-p-val236-met237insile), [AK2 c.330+5G>A](/variant/ak2-c-330-plus-5g-a), [AK2 c.498+1G>A](/variant/ak2-c-498-plus-1g-a), [AK2 p.Ala182Asp](/variant/ak2-p-ala182asp), [AK2 p.Arg103Trp](/variant/ak2-p-arg103trp), [AK2 p.Arg175Pro](/variant/ak2-p-arg175pro).

### 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 1384263). 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.*