# NM_001625.4(AK2):c.121G>T (p.Val41Phe)

https://sugi.bio/variant/ak2-p-val41phe

## Summary

**AK2 p.Val41Phe (c.121G>T)** is classified **Uncertain significance** in AK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-18). AlphaMissense: likely pathogenic (0.8636); Very rare (popmax 0.000508%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.000508%, nfe)

## 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 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 | [AK2](https://sugi.bio/atlas/gene/AK2/) |
| Protein change (HGVS p.) | p.Val41Phe |
| Coding change (HGVS c.) | c.121G>T |
| MANE Select transcript | [NM_001625](https://www.ncbi.nlm.nih.gov/nuccore/NM_001625) |
| Variant type | single nucleotide variant |
| Location | chr1:33024540-33024540 (GRCh38) |
| ClinVar | [VCV4030332](https://www.ncbi.nlm.nih.gov/clinvar/variation/4030332/) |

**All HGVS expressions:** `LRG_133:g.17352G>T`, `LRG_133t1:c.121G>T`, `NC_000001.10:g.33490141C>A`, `NC_000001.11:g.33024540C>A`, `NG_016269.1:g.17352G>T`, `NM_001199199.3:c.121G>T`, `NM_001319139.3:c.-24G>T`, `NM_001319140.2:c.-24G>T`, `NM_001319141.3:c.121G>T`, `NM_001319142.3:c.94-2837G>T`, `NM_001319143.2:c.121G>T`, `NM_001625.4:c.121G>T`, `NM_013411.5:c.121G>T`, `NR_134976.3:n.176G>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8636)
- REVEL 0.662 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -10.256 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **acceptor gain** (Δ 0.21) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 2.202, GERP 1.69, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 26.4**. 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 0.85** across the covering region of the MANE Select transcript (33,013,184–33,036,828), spanning 23,644 bp. Chi-square p 0.0069. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.21**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.21**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.000508%** (nfe) · FAF95 0.000183% · FAF99 0.00012% · 6/1,180,012 in the highest group · 6/1,614,150 alleles overall — very rare (popmax 0.000508%, 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}


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 2025-03-18.

**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 | 2025-03-18 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related AK2 variant pages (same residue, condition, or type): [AK2 p.Ala212Thr](/variant/ak2-p-ala212thr), [AK2 p.Ala2Val](/variant/ak2-p-ala2val), [AK2 p.Ala32Thr](/variant/ak2-p-ala32thr), [AK2 p.Gly169Arg](/variant/ak2-p-gly169arg), [AK2 p.His43Arg](/variant/ak2-p-his43arg), [AK2 p.Leu224Val](/variant/ak2-p-leu224val), [AK2 p.Lys93Glu](/variant/ak2-p-lys93glu), [AK2 p.Pro158Ser](/variant/ak2-p-pro158ser).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2026-10-14); 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 4030332). 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.*