# NM_207315.4(CMPK2):c.181del (p.Arg61fs)

https://sugi.bio/variant/cmpk2-p-arg61fs

## Summary

**CMPK2 p.Arg61fs (c.181del)** is classified **Likely pathogenic** in CMPK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-01). No allele count reported in gnomAD v4.1 (AN 1,273,380); Associated with basal ganglia calcification, idiopathic, 10, autosomal recessive.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition · no allele count reported in gnomAD v4.1 (AN 1,273,380)

## For patients & families {#patients}

This is a change in the CMPK2 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to basal ganglia calcification, idiopathic, 10, autosomal recessive.

*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 dominant, Autosomal recessive, Not applicable |
| Age of onset (of this condition) | Adult |
| Diagnostic panels | CMPK2 is a diagnostic-grade gene on 7 Genomics England panels |

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

- Mask-like facies — Frequent (79-30%)
- Psychosis — Frequent (79-30%)
- Dementia — Frequent (79-30%)
- Anxiety — Frequent (79-30%)
- Personality changes — Frequent (79-30%)
- Seizure — Frequent (79-30%)
- Choreoathetosis — Frequent (79-30%)
- Tremor — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0027334/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CMPK2](https://sugi.bio/atlas/gene/CMPK2/) |
| Protein change (HGVS p.) | p.Arg61fs |
| Coding change (HGVS c.) | c.181del |
| MANE Select transcript | [NM_207315](https://www.ncbi.nlm.nih.gov/nuccore/NM_207315) |
| Variant type | Deletion |
| Location | chr2:6865516-6865516 (GRCh38) |
| ClinVar | [VCV4850568](https://www.ncbi.nlm.nih.gov/clinvar/variation/4850568/) |

**All HGVS expressions:** `NC_000002.11:g.7005651del`, `NC_000002.12:g.6865520del`, `NG_166043.1:g.403del`, `NM_001256477.1:c.181del`, `NM_001256478.1:c.181del`, `NM_207315.4:c.181del`, `NM_207315.4:c.181delC`

## 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 1.659, GERP -0.67, phastCons 0.313 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.708, pLI 7.1598e-13. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 1 of 5**, so the transcript is predicted to undergo NMD.
- 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: **no allele count reported in gnomAD v4.1 (AN 1,273,380)** — 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}

**CMPK2** population constraint: LOEUF 1.708, pLI 7.1598e-13, missense-Z -2.6199. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 87.26, 66% of residues very-high.

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

*Describes the biological roles of CMPK2 (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:** CMPK2's established molecular role includes nucleoside diphosphate kinase activity.


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

**Molecular function:** nucleoside diphosphate kinase activity, UMP kinase activity.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| First Genomix Gene Laboratory, Genetic Diagnostics Department | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-08-01 |

## Associated conditions {#conditions}

[basal ganglia calcification, idiopathic, 10, autosomal recessive](https://sugi.bio/atlas/disease/basal-ganglia-calcification-idiopathic-10-autosomal-recessive/).

**Reported phenotype names (ClinVar):** Basal ganglia calcification, idiopathic, 10, autosomal recessive.

## Similar variants {#similar}

Related CMPK2 variant pages (same residue, condition, or type): [CMPK2 p.Arg61Cys](/variant/cmpk2-p-arg61cys), [CMPK2 p.Arg61Ser](/variant/cmpk2-p-arg61ser), [CMPK2 p.Met1Leu](/variant/cmpk2-p-met1leu), [CMPK2 p.Met1Thr](/variant/cmpk2-p-met1thr), [CMPK2 p.Tyr414Cys](/variant/cmpk2-p-tyr414cys).

### 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 4850568). 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.*