# NM_004341.5(CAD):c.933_934del (p.Phe312fs)

https://sugi.bio/variant/cad-p-phe312fs

## Summary

**CAD p.Phe312fs (c.933_934del)** is classified **Pathogenic** in CAD (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-17). No gnomAD frequency available for this variant; Associated with developmental and epileptic encephalopathy, 50.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2465293335 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CAD gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to developmental and epileptic encephalopathy, 50.

*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 |
| Diagnostic panels | CAD is a diagnostic-grade gene on 9 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0013621/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CAD](https://sugi.bio/atlas/gene/CAD/) |
| Protein change (HGVS p.) | p.Phe312fs |
| Coding change (HGVS c.) | c.933_934del |
| MANE Select transcript | [NM_004341](https://www.ncbi.nlm.nih.gov/nuccore/NM_004341) |
| dbSNP | [rs2465293335](https://www.ncbi.nlm.nih.gov/snp/rs2465293335/) |
| Variant type | Microsatellite |
| Location | chr2:27223682-27223683 (GRCh38) |
| ClinVar | [VCV3254721](https://www.ncbi.nlm.nih.gov/clinvar/variation/3254721/) |

**All HGVS expressions:** `NC_000002.11:g.27446550CT[2]`, `NC_000002.12:g.27223682CT[2]`, `NG_046394.1:g.11293CT[2]`, `NM_001306079.2:c.933_934del`, `NM_004341.5:c.933_934del`

## 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 4.064, GERP 2.16, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.409, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 7 of 44**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite 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}

**CAD** population constraint: LOEUF 0.409, pLI 1, missense-Z 5.7821. *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):

- **developmental and epileptic encephalopathy, 50** — Definitive (AR)

## Protein context {#protein}

Residue **312** lies in the glutamine amidotransferase type-1 domain; the 'gatase (glutamine amidotransferase)' region.

AlphaFold model confidence (whole protein): pLDDT 87.25, 62% of residues very-high.

**57 experimental structure(s)** (PDB): [4BY3](https://www.rcsb.org/structure/4BY3), [4C6B](https://www.rcsb.org/structure/4C6B), [4C6C](https://www.rcsb.org/structure/4C6C), [4C6D](https://www.rcsb.org/structure/4C6D), [4C6E](https://www.rcsb.org/structure/4C6E), [4C6F](https://www.rcsb.org/structure/4C6F) — incl. mutant structure 4C6N.

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

*Describes the biological roles of CAD (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:** CAD's established molecular role includes dihydroorotase activity. p.Phe312fs falls in the glutamine amidotransferase type-1 domain.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Pyrimidine biosynthesis](https://reactome.org/content/detail/R-HSA-500753) | curated |

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

**Molecular function:** dihydroorotase activity, zinc ion binding, enzyme binding, identical protein binding.

**Biological process:** 'de novo' pyrimidine nucleobase biosynthetic process, UDP biosynthetic process, 'de novo' UMP biosynthetic process.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-07-17.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2023-07-17 |

## Associated conditions {#conditions}

[developmental and epileptic encephalopathy, 50](https://sugi.bio/atlas/disease/developmental-and-epileptic-encephalopathy-50/).

**Reported phenotype names (ClinVar):** Developmental and epileptic encephalopathy, 50, Epileptic encephalopathy, early infantile, 50.

## Similar variants {#similar}

Related CAD variant pages (same residue, condition, or type): [CAD p.Phe312=](/variant/cad-p-phe312), [CAD p.Arg1789Ter](/variant/cad-p-arg1789ter), [CAD p.Arg1810Gln](/variant/cad-p-arg1810gln), [CAD p.Arg191Ter](/variant/cad-p-arg191ter), [CAD p.Gln1604Ter](/variant/cad-p-gln1604ter), [CAD p.Gln1913fs](/variant/cad-p-gln1913fs), [CAD p.Met33Arg](/variant/cad-p-met33arg), [CAD c.4315-3C>T](/variant/cad-c-4315-minus-3c-t).

### 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 3254721). 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.*