# NM_001625.4(AK2):c.87G>A (p.Gly29=)

https://sugi.bio/variant/ak2-p-gly29

## Summary

**AK2 p.Gly29= (c.87G>A)** is classified **Likely benign** in AK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-03). Very rare (popmax 0.00135%, afr); Associated with reticular dysgenesis.

**At a glance:** Likely benign · review: Single submitter · rsID rs564282489 · 1 submitter · 1 linked condition · very rare (popmax 0.00135%, afr)

## For patients & families {#patients}

This is a change in the AK2 gene that is classified as likely benign — not considered disease-causing, 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.Gly29= |
| Coding change (HGVS c.) | c.87G>A |
| MANE Select transcript | [NM_001625](https://www.ncbi.nlm.nih.gov/nuccore/NM_001625) |
| dbSNP | [rs564282489](https://www.ncbi.nlm.nih.gov/snp/rs564282489/) |
| Variant type | single nucleotide variant |
| Location | chr1:33036742-33036742 (GRCh38) |
| ClinVar | [VCV2977817](https://www.ncbi.nlm.nih.gov/clinvar/variation/2977817/) |

**All HGVS expressions:** `LRG_133:g.5150G>A`, `LRG_133t1:c.87G>A`, `NC_000001.10:g.33502343C>T`, `NC_000001.11:g.33036742C>T`, `NG_016269.1:g.5150G>A`, `NG_163121.1:g.141C>T`, `NM_001199199.3:c.87G>A`, `NM_001319139.3:c.-176G>A`, `NM_001319140.2:c.-176G>A`, `NM_001319141.3:c.87G>A`, `NM_001319142.3:c.87G>A`, `NM_001319143.2:c.87G>A`, `NM_001625.4:c.87G>A`, `NM_013411.5:c.87G>A`, `NR_037591.1:n.170G>A`, `NR_037592.1:n.170G>A`, `NR_134976.3:n.142G>A`

## 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 0.573, GERP -5.54, phastCons 0.968 — weakly conserved position
- CADD: **PHRED 10.62**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.31 donor gain), 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 **0.00135%** (afr) · 1/74,090 in the highest group · 3/1,578,016 alleles overall — very rare (popmax 0.00135%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00164% | 61,048 |
| African / African-American (grpmax) | 0.00135% | 74,090 |
| European (non-Finnish) | 8.63e-05% | 1,158,514 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **29** lies in an α-helix; a binding site.

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 benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-06-03.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-06-03 |

## 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.

## Same-residue context {#hotspot}

Residue **29** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [AK2 p.Gly29fs](/variant/ak2-p-gly29fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related AK2 variant pages (same residue, condition, or type): [AK2 p.Gly29fs](/variant/ak2-p-gly29fs), [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), [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 2977817). 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.*