# NM_001625.4(AK2):c.307C>T (p.Arg103Trp)

https://sugi.bio/variant/ak2-p-arg103trp

## Summary

**AK2 p.Arg103Trp (c.307C>T)** is classified **Pathogenic/Likely pathogenic** in AK2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-01). AlphaMissense: likely pathogenic (0.9896); Very rare (popmax 0.00223%, eas); Associated with severe combined immunodeficiency.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs267606648 · 4 submitters · 2 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the AK2 gene that is considered likely disease-causing, submitted by 4 submitters, and is linked to severe combined immunodeficiency.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 44 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007628/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.Arg103Trp |
| Coding change (HGVS c.) | c.307C>T |
| MANE Select transcript | [NM_001625](https://www.ncbi.nlm.nih.gov/nuccore/NM_001625) |
| dbSNP | [rs267606648](https://www.ncbi.nlm.nih.gov/snp/rs267606648/) |
| Variant type | single nucleotide variant |
| Location | chr1:33021616-33021616 (GRCh38) |
| ClinVar | [VCV18260](https://www.ncbi.nlm.nih.gov/clinvar/variation/18260/) |

**All HGVS expressions:** `LRG_133:g.20276C>T`, `NC_000001.10:g.33487217G>A`, `NC_000001.11:g.33021616G>A`, `NG_016269.1:g.20276C>T`, `NM_001199199.3:c.307C>T`, `NM_001319139.3:c.163C>T`, `NM_001319140.2:c.163C>T`, `NM_001319141.3:c.307C>T`, `NM_001319142.3:c.181C>T`, `NM_001319143.2:c.307C>T`, `NM_001625.4:c.307C>T`, `NM_013411.5:c.307C>T`, `NR_134976.3:n.362C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9896) — concordant with the pathogenic call
- REVEL 0.766 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -17.834 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.468, GERP 2.77, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 33.0**. 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.*
- 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · FAF95 6.8e-05% · FAF99 1.9e-05% · 1/44,900 in the highest group · 5/1,613,962 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00223% | 44,900 |
| African / African-American | 0.00133% | 74,914 |
| European (non-Finnish) | 0.000254% | 393,318 |

*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 **103** lies in a binding site; a UniProt-annotated variant site (in rdys).

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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-11-01.

**Submitter consensus:** conflicting (3 Pathogenic, 1 Likely pathogenic).

**Submission history:** 4 submissions (2009–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Likely pathogenic | criteria provided, single submitter | clinical testing | 2018-09-26 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2009-01-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-09-16 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-11-01 |

## Associated conditions {#conditions}

[severe combined immunodeficiency](https://sugi.bio/atlas/disease/severe-combined-immunodeficiency/), [reticular dysgenesis](https://sugi.bio/atlas/disease/reticular-dysgenesis/).

**Reported phenotype names (ClinVar):** Severe combined immunodeficiency disease, Reticular dysgenesis, Severe combined immunodeficiency, Severe Combined Immune Deficiency, 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.Arg103=](/variant/ak2-p-arg103), [AK2 p.Arg103Pro](/variant/ak2-p-arg103pro), [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.Arg175Pro](/variant/ak2-p-arg175pro), [AK2 p.Met1Val](/variant/ak2-p-met1val), [AK2 p.Ala212Thr](/variant/ak2-p-ala212thr).

### 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 18260). 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.*