# NM_004341.5(CAD):c.1158C>T (p.Pro386=)

https://sugi.bio/variant/cad-p-pro386

## Summary

**CAD p.Pro386= (c.1158C>T)** is classified **Likely benign** in CAD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-19). Ultra-rare (popmax 0.0466%, amr).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs541054613 · 3 submitters · ultra-rare (popmax 0.0466%, amr)

## For patients & families {#patients}

This is a change in the CAD gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters.

*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 | [CAD](https://sugi.bio/atlas/gene/CAD/) |
| Protein change (HGVS p.) | p.Pro386= |
| Coding change (HGVS c.) | c.1158C>T |
| MANE Select transcript | [NM_004341](https://www.ncbi.nlm.nih.gov/nuccore/NM_004341) |
| dbSNP | [rs541054613](https://www.ncbi.nlm.nih.gov/snp/rs541054613/) |
| Variant type | single nucleotide variant |
| Location | chr2:27224394-27224394 (GRCh38) |
| ClinVar | [VCV726316](https://www.ncbi.nlm.nih.gov/clinvar/variation/726316/) |

**All HGVS expressions:** `NC_000002.11:g.27447262C>T`, `NC_000002.12:g.27224394C>T`, `NG_046394.1:g.12005C>T`, `NM_001306079.2:c.1158C>T`, `NM_004341.5:c.1158C>T`

## 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 -2.625, GERP -4.08 — fast-evolving / accelerated position
- CADD: **PHRED 0.901**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.29 acceptor 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 **0.0466%** (amr) · FAF95 0.0331% · FAF99 0.0286% · 28/60,024 in the highest group · 319/1,614,192 alleles overall — ultra-rare (popmax 0.0466%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0466% | 2,144 |
| Remaining individuals (not grpmax-eligible) | 0.0256% | 3,907 |
| European (non-Finnish) | 0.0228% | 4,387 |
| African / African-American | 0.00666% | 15,012 |
| East Asian | 0.00223% | 44,884 |

*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 **386** lies in the 'linker' 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.Pro386= falls in the linker region.


### 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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-19.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2019–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-06-10 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-19 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-03-01 |

**Reported phenotype names (ClinVar):** not provided, CAD-related disorder, none provided, CAD-related condition.

## Similar variants {#similar}

Related CAD variant pages (same residue, condition, or type): [CAD p.Pro386Ser](/variant/cad-p-pro386ser), [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.1254+6G>A](/variant/cad-c-1254-plus-6g-a), [CAD c.2032-3C>T](/variant/cad-c-2032-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 726316). 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.*