# NM_004341.5(CAD):c.859C>T (p.Arg287Cys)

https://sugi.bio/variant/cad-p-arg287cys

## Summary

**CAD p.Arg287Cys (c.859C>T)** is classified **Uncertain significance** in CAD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-06-13). AlphaMissense: likely benign (0.2172); Ultra-rare (popmax 0.0174%, mid); Associated with developmental and epileptic encephalopathy, 50.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs753478495 · 2 submitters · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0174%, mid)

## For patients & families {#patients}

This is a change in the CAD gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, 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.Arg287Cys |
| Coding change (HGVS c.) | c.859C>T |
| MANE Select transcript | [NM_004341](https://www.ncbi.nlm.nih.gov/nuccore/NM_004341) |
| dbSNP | [rs753478495](https://www.ncbi.nlm.nih.gov/snp/rs753478495/) |
| Variant type | single nucleotide variant |
| Location | chr2:27223612-27223612 (GRCh38) |
| ClinVar | [VCV1028734](https://www.ncbi.nlm.nih.gov/clinvar/variation/1028734/) |

**All HGVS expressions:** `NC_000002.11:g.27446480C>T`, `NC_000002.12:g.27223612C>T`, `NG_046394.1:g.11223C>T`, `NM_001306079.2:c.859C>T`, `NM_004341.5:c.859C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.2172)
- REVEL 0.931 (moderately pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -11.447 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** REVEL and SaProt call this damaging; AlphaMissense does not
- Conservation: phyloP 7.693, GERP 2.16, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 34.0**. 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 0.90** across the covering region of the MANE Select transcript (27,223,596–27,224,421), spanning 825 bp. Chi-square p 0.23. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0174%** (mid) · FAF95 0.00143% · FAF99 0.000971% · 1/5,750 in the highest group · 32/1,613,564 alleles overall — ultra-rare (popmax 0.0174%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0174% | 5,750 |
| Admixed American | 0.005% | 20,001 |
| South Asian | 0.00439% | 22,762 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,229 |
| East Asian | 0.00223% | 44,886 |
| European (non-Finnish) | 0.00178% | 56,192 |

*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 **287** 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.Arg287Cys 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2022-06-13.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2019–2022); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-09-20 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-06-13 |

## 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, not provided, Epileptic encephalopathy, early infantile, 50, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## Similar variants {#similar}

Related CAD variant pages (same residue, condition, or type): [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.Met33Arg](/variant/cad-p-met33arg), [CAD c.4315-3C>T](/variant/cad-c-4315-minus-3c-t), [CAD c.996-13A>G](/variant/cad-c-996-minus-13a-g), [CAD c.996-4A>G](/variant/cad-c-996-minus-4a-g).

### 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 1028734). 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.*