# NM_001277.3(CHKA):c.14dup (p.Cys6fs)

https://sugi.bio/variant/chka-p-cys6fs

## Summary

**CHKA p.Cys6fs (c.14dup)** is classified **Likely pathogenic** in CHKA (ClinVar, Single submitter, 2 submitters; last evaluated 2024-08-08). No gnomAD frequency available for this variant; Associated with microcephaly.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2153034844 · 2 submitters · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CHKA gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to microcephaly.

*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 | 1 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CHKA](https://sugi.bio/atlas/gene/CHKA/) |
| Protein change (HGVS p.) | p.Cys6fs |
| Coding change (HGVS c.) | c.14dup |
| MANE Select transcript | [NM_001277](https://www.ncbi.nlm.nih.gov/nuccore/NM_001277) |
| dbSNP | [rs2153034844](https://www.ncbi.nlm.nih.gov/snp/rs2153034844/) |
| Variant type | Duplication |
| Location | chr11:68121163-68121164 (GRCh38) |
| ClinVar | [VCV1325847](https://www.ncbi.nlm.nih.gov/clinvar/variation/1325847/) |

**All HGVS expressions:** `NC_000011.10:g.68121165dup`, `NC_000011.9:g.67888632dup`, `NM_001277.3:c.14dup`, `NM_001376219.1:c.14dup`, `NM_001376220.1:c.14dup`, `NM_001376221.1:c.-351dup`, `NM_001376222.1:c.-351dup`, `NM_212469.2:c.14dup`, `NR_164782.1:n.225dup`

## Computational & population evidence {#evidence}

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

- **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 8.192, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.926, pLI 0.00039274. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 1 of 12**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — 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}

**CHKA** population constraint: LOEUF 0.926, pLI 0.00039274, missense-Z -0.64702. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **6** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 83.95, 72% of residues very-high.

**26 experimental structure(s)** (PDB): [2CKO](https://www.rcsb.org/structure/2CKO), [2CKP](https://www.rcsb.org/structure/2CKP), [2CKQ](https://www.rcsb.org/structure/2CKQ), [2I7Q](https://www.rcsb.org/structure/2I7Q), [3F2R](https://www.rcsb.org/structure/3F2R), [3G15](https://www.rcsb.org/structure/3G15).

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

*Describes the biological roles of CHKA (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:** CHKA's established molecular role includes choline kinase activity. p.Cys6fs falls in the disordered region.


### Pathways affected {#pathways}

CHKA participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Synthesis of PC](https://reactome.org/content/detail/R-HSA-1483191) | curated |
| [Synthesis of PE](https://reactome.org/content/detail/R-HSA-1483213) | curated |

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

**Molecular function:** choline kinase activity, ethanolamine kinase activity, protein tyrosine kinase activity, protein homodimerization activity.

**Biological process:** phosphatidylethanolamine biosynthetic process, phosphatidylcholine biosynthetic process, cellular response to glucose starvation, lipid droplet disassembly.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-08-08.

**Submitter consensus:** conflicting (2 Likely pathogenic, 1 Pathogenic).

**Submission history:** 3 submissions (2021–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Human Genetics, University of Leipzig Medical Center | Likely pathogenic | criteria provided, single submitter | research | 2021-10-15 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2022-09-01 |
| Institute of Human Genetics, University of Leipzig Medical Center | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-08-08 |

## Associated conditions {#conditions}

[microcephaly](https://sugi.bio/atlas/disease/microcephaly/), [neurodevelopmental disorder with microcephaly, movement abnormalities, and seizures](https://sugi.bio/atlas/disease/neurodevelopmental-disorder-with-microcephaly-movement-abnormalities-and-seizures/).

**Reported phenotype names (ClinVar):** Microcephaly, Seizure, Severe intellectual disability, Neurodevelopmental disorder with microcephaly, movement abnormalities, and seizures, Microcephaly (disease), Seizures.

## Similar variants {#similar}

Related CHKA variant pages (same residue, condition, or type): [CHKA p.Glu230Lys](/variant/chka-p-glu230lys), [CHKA p.Arg141Trp](/variant/chka-p-arg141trp), [CHKA p.Phe341Leu](/variant/chka-p-phe341leu), [CHKA p.Pro194Ser](/variant/chka-p-pro194ser), [CHKA p.63LP[3]](/variant/chka-p-63lp-3), [CHKA p.Arg204Leu](/variant/chka-p-arg204leu), [CHKA p.Met1Thr](/variant/chka-p-met1thr), [CHKA p.Pro64Gln](/variant/chka-p-pro64gln).

### 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 1325847). 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.*