# NM_015891.3(CDC40):c.967C>T (p.Arg323Cys)

https://sugi.bio/variant/cdc40-p-arg323cys

## Summary

**CDC40 p.Arg323Cys (c.967C>T)** is classified **Uncertain significance** in CDC40 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-03). AlphaMissense: likely benign (0.2192); Very rare (popmax 0.00401%, afr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs773612198 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00401%, afr)

## For patients & families {#patients}

This is a change in the CDC40 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 | [CDC40](https://sugi.bio/atlas/gene/CDC40/) |
| Protein change (HGVS p.) | p.Arg323Cys |
| Coding change (HGVS c.) | c.967C>T |
| MANE Select transcript | [NM_015891](https://www.ncbi.nlm.nih.gov/nuccore/NM_015891) |
| dbSNP | [rs773612198](https://www.ncbi.nlm.nih.gov/snp/rs773612198/) |
| Variant type | single nucleotide variant |
| Location | chr6:110215310-110215310 (GRCh38) |
| ClinVar | [VCV2268998](https://www.ncbi.nlm.nih.gov/clinvar/variation/2268998/) |

**All HGVS expressions:** `NC_000006.11:g.110536513C>T`, `NC_000006.12:g.110215310C>T`, `NM_015891.3:c.967C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2192)
- REVEL 0.425 (indeterminate)
- SaProt LLR -12.08 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL makes no call
- Conservation: phyloP 7.651, GERP 1.56, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 33.0**. 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 0.77** across the covering region of the MANE Select transcript (110,180,445–110,219,758), spanning 39,313 bp. Chi-square p 5.5e-07. 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 (C>G, Δ0.20 acceptor loss), 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 **0.00401%** (afr) · FAF95 0.00106% · FAF99 0.000495% · 3/74,808 in the highest group · 20/1,613,016 alleles overall — very rare (popmax 0.00401%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00676% | 14,793 |
| African / African-American (grpmax) | 0.00401% | 24,936 |
| South Asian | 0.00329% | 30,353 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,448 |
| European (non-Finnish) | 0.000933% | 107,208 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**CDC40** population constraint: LOEUF 0.491, pLI 0.97911, missense-Z 2.0922. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 86.76, 71% of residues very-high.

**30 experimental structure(s)** (PDB): [5MQF](https://www.rcsb.org/structure/5MQF), [5XJC](https://www.rcsb.org/structure/5XJC), [5YZG](https://www.rcsb.org/structure/5YZG), [5Z56](https://www.rcsb.org/structure/5Z56), [5Z57](https://www.rcsb.org/structure/5Z57), [6FF4](https://www.rcsb.org/structure/6FF4) — incl. mutant structure 8CH6.

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

*Describes the biological roles of CDC40 (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:** CDC40's established molecular role includes RNA binding. In Reactome, CDC40 is annotated in disease pathway(s) including **Dengue Virus-Host Interactions**.

**Disease mechanism (Reactome):** CDC40 loss or alteration is curated in [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481).

### Pathways affected {#pathways}

CDC40 participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481) | curated |
| [Transport of Mature mRNA derived from an Intron-Containing Transcript](https://reactome.org/content/detail/R-HSA-159236) | curated |
| [mRNA 3'-end processing](https://reactome.org/content/detail/R-HSA-72187) | curated |
| [mRNA Polyadenylation](https://reactome.org/content/detail/R-HSA-9770562) | curated |
| [mRNA Splicing - Major Pathway](https://reactome.org/content/detail/R-HSA-72163) | curated |
| [RNA Polymerase II Transcription Termination](https://reactome.org/content/detail/R-HSA-73856) | other |

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

**Molecular function:** RNA binding.

**Biological process:** mRNA splicing, via spliceosome, embryonic brain development.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-01-03.

**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 | 2022-01-03 |

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

## Similar variants {#similar}

Related CDC40 variant pages (same residue, condition, or type): [CDC40 p.Ala33Gly](/variant/cdc40-p-ala33gly), [CDC40 p.Ala466Thr](/variant/cdc40-p-ala466thr), [CDC40 p.Arg129Lys](/variant/cdc40-p-arg129lys), [CDC40 p.Arg322Trp](/variant/cdc40-p-arg322trp), [CDC40 p.Asn382His](/variant/cdc40-p-asn382his), [CDC40 p.Asn430Lys](/variant/cdc40-p-asn430lys), [CDC40 p.Asn497Thr](/variant/cdc40-p-asn497thr), [CDC40 p.Asn97Thr](/variant/cdc40-p-asn97thr).

### 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 2268998). 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.*