# NM_022766.6(CERK):c.785T>C (p.Val262Ala)

https://sugi.bio/variant/cerk-p-val262ala

## Summary

**CERK p.Val262Ala (c.785T>C)** is classified **Uncertain significance** in CERK (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-11). AlphaMissense: likely benign (0.3053); Very rare (popmax 8.69e-05%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 8.69e-05%, nfe)

## For patients & families {#patients}

This is a change in the CERK gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [CERK](https://sugi.bio/atlas/gene/CERK/) |
| Protein change (HGVS p.) | p.Val262Ala |
| Coding change (HGVS c.) | c.785T>C |
| MANE Select transcript | [NM_022766](https://www.ncbi.nlm.nih.gov/nuccore/NM_022766) |
| Variant type | single nucleotide variant |
| Location | chr22:46701641-46701641 (GRCh38) |
| ClinVar | [VCV3491017](https://www.ncbi.nlm.nih.gov/clinvar/variation/3491017/) |

**All HGVS expressions:** `NC_000022.10:g.47097538A>G`, `NC_000022.11:g.46701641A>G`, `NM_022766.6:c.785T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.3053)
- REVEL 0.267 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -9.066 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 10.472, GERP 1.55, phastCons 0.993 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.2**. 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 0.94** across the covering region of the MANE Select transcript (46,687,137–46,738,148), spanning 51,011 bp. Chi-square p 0.099. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (A>T, Δ0.27 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 **8.69e-05%** (nfe) · 1/1,150,248 in the highest group · 1/1,404,652 alleles overall — very rare (popmax 8.69e-05%, 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}

**CERK** population constraint: LOEUF 0.829, pLI 2.2397e-06, missense-Z 0.27625. *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 **262** lies in the dagkc domain.

AlphaFold model confidence (whole protein): pLDDT 88.86, 74% of residues very-high.

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

*Describes the biological roles of CERK (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:** CERK's established molecular role includes magnesium ion binding. p.Val262Ala falls in the dagkc domain.


### Pathways affected {#pathways}

CERK participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Glycosphingolipid biosynthesis](https://reactome.org/content/detail/R-HSA-9840309) | curated |

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

**Molecular function:** magnesium ion binding, ceramide kinase activity.

**Biological process:** ceramide metabolic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-08-11.

**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 | 2024-08-11 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related CERK variant pages (same residue, condition, or type): [CERK p.Val262Ile](/variant/cerk-p-val262ile), [CERK p.His113=](/variant/cerk-p-his113), [CERK p.Pro509=](/variant/cerk-p-pro509), [CERK p.Thr461Met](/variant/cerk-p-thr461met), [CERK p.Ala215Thr](/variant/cerk-p-ala215thr), [CERK p.Ala215Val](/variant/cerk-p-ala215val), [CERK p.Ala238Ser](/variant/cerk-p-ala238ser), [CERK p.Ala238Thr](/variant/cerk-p-ala238thr).

### 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 3491017). 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.*