# NM_001625.4(AK2):c.575del (p.Thr192fs)

https://sugi.bio/variant/ak2-p-thr192fs

## Summary

**AK2 p.Thr192fs (c.575del)** is classified **Likely pathogenic** in AK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-08). Very rare (popmax 8.48e-05%, nfe); Associated with AK2-related disorder.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the AK2 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to AK2-related disorder.

*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 | [AK2](https://sugi.bio/atlas/gene/AK2/) |
| Protein change (HGVS p.) | p.Thr192fs |
| Coding change (HGVS c.) | c.575del |
| MANE Select transcript | [NM_001625](https://www.ncbi.nlm.nih.gov/nuccore/NM_001625) |
| Variant type | Deletion |
| Location | chr1:33013326-33013326 (GRCh38) |
| ClinVar | [VCV4965666](https://www.ncbi.nlm.nih.gov/clinvar/variation/4965666/) |

**All HGVS expressions:** `LRG_133:g.28566del`, `LRG_133t1:c.575del`, `NC_000001.10:g.33478927del`, `NC_000001.11:g.33013326del`, `NG_016269.1:g.28566del`, `NM_001199199.3:c.551del`, `NM_001319139.3:c.431del`, `NM_001319140.2:c.431del`, `NM_001319141.3:c.575del`, `NM_001319142.3:c.449del`, `NM_001319143.2:c.*78del`, `NM_001625.4:c.575del`, `NM_013411.5:c.575del`, `NR_134976.3:n.535del`

## 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 -0.015, GERP -5.47, phastCons 0.031 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- 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 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 **8.48e-05%** (nfe) · 1/1,179,936 in the highest group · 1/1,461,796 alleles overall — very rare (popmax 8.48e-05%, nfe).

*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}

Residue **192** lies in an α-helix.

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}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-11-08.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-11-08 |

## Associated conditions {#conditions}

[AK2-related disorder](https://sugi.bio/atlas/disease/ak2-related-disorder/).

**Reported phenotype names (ClinVar):** AK2-related disorder, AK2-related condition.

## Similar variants {#similar}

Related AK2 variant pages (same residue, condition, or type): [AK2 p.Thr192Asn](/variant/ak2-p-thr192asn), [AK2 p.Ala182Asp](/variant/ak2-p-ala182asp), [AK2 c.-6G>A](/variant/ak2-c-minus-6g-a), [AK2 c.*2G>A](/variant/ak2-c-star-2g-a), [AK2 p.Ala212_Ter240delinsXaa](/variant/ak2-p-ala212-ter240delinsxaa), [AK2 p.Gly205fs](/variant/ak2-p-gly205fs), [AK2 p.Tyr152fs](/variant/ak2-p-tyr152fs), [AK2 p.Val219fs](/variant/ak2-p-val219fs).

### 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 4965666). 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.*