# NM_001256875.2(CDCA8):c.419C>T (p.Ala140Val)

https://sugi.bio/variant/cdca8-p-ala140val

## Summary

**CDCA8 p.Ala140Val (c.419C>T)** is classified **Uncertain significance** in CDCA8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-01). AlphaMissense: likely benign (0.0891); Very rare (popmax 0.00223%, eas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the CDCA8 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 | [CDCA8](https://sugi.bio/atlas/gene/CDCA8/) |
| Protein change (HGVS p.) | p.Ala140Val |
| Coding change (HGVS c.) | c.419C>T |
| MANE Select transcript | [NM_001256875](https://www.ncbi.nlm.nih.gov/nuccore/NM_001256875) |
| Variant type | single nucleotide variant |
| Location | chr1:37700517-37700517 (GRCh38) |
| ClinVar | [VCV3488587](https://www.ncbi.nlm.nih.gov/clinvar/variation/3488587/) |

**All HGVS expressions:** `NC_000001.10:g.38166189C>T`, `NC_000001.11:g.37700517C>T`, `NM_001256875.2:c.419C>T`, `NM_018101.4:c.419C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0891)
- REVEL 0.059 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.243 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor gain** (Δ 0.35) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 1.597, GERP -0.406, phastCons 0.025 — weakly conserved position
- CADD: **PHRED 20.7**. 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 0.80** across the covering region of the MANE Select transcript (37,692,691–37,708,363), spanning 15,672 bp. Chi-square p 0.00025. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.01**, acceptor gain **0.00**, donor gain **0.35**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.35**.
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · 1/44,820 in the highest group · 3/1,597,084 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00223% | 44,820 |
| Admixed American | 0.00167% | 59,960 |
| African / African-American | 0.00134% | 74,614 |

*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}

**CDCA8** population constraint: LOEUF 0.944, pLI 0.00054742, missense-Z 1.808. *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 **140** lies in the 'required for interaction with senp3' region; the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 68.28, 21% of residues very-high.

**15 experimental structure(s)** (PDB): [2KDD](https://www.rcsb.org/structure/2KDD), [2QFA](https://www.rcsb.org/structure/2QFA), [2RAW](https://www.rcsb.org/structure/2RAW), [2RAX](https://www.rcsb.org/structure/2RAX), [6YIE](https://www.rcsb.org/structure/6YIE), [6YIF](https://www.rcsb.org/structure/6YIF).

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

*Describes the biological roles of CDCA8 (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.*


### Pathways affected {#pathways}

CDCA8 participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Amplification  of signal from unattached  kinetochores via a MAD2  inhibitory signal](https://reactome.org/content/detail/R-HSA-141444) | curated |
| [EML4 and NUDC in mitotic spindle formation](https://reactome.org/content/detail/R-HSA-9648025) | curated |
| [Mitotic Prometaphase](https://reactome.org/content/detail/R-HSA-68877) | curated |
| [RHO GTPases Activate Formins](https://reactome.org/content/detail/R-HSA-5663220) | curated |
| [Resolution of Sister Chromatid Cohesion](https://reactome.org/content/detail/R-HSA-2500257) | curated |
| [SUMOylation of DNA replication proteins](https://reactome.org/content/detail/R-HSA-4615885) | curated |
| [Separation of Sister Chromatids](https://reactome.org/content/detail/R-HSA-2467813) | curated |

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

**Biological process:** mitotic metaphase chromosome alignment, chromosome organization.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-01.

**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 | 2024-10-01 |

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

## Similar variants {#similar}

Related CDCA8 variant pages (same residue, condition, or type): [CDCA8 p.Ala173Val](/variant/cdca8-p-ala173val), [CDCA8 p.Arg166Cys](/variant/cdca8-p-arg166cys), [CDCA8 p.Arg176Gln](/variant/cdca8-p-arg176gln), [CDCA8 p.Arg210Trp](/variant/cdca8-p-arg210trp), [CDCA8 p.Arg240Gln](/variant/cdca8-p-arg240gln), [CDCA8 p.Arg277Gln](/variant/cdca8-p-arg277gln), [CDCA8 p.Arg35Gln](/variant/cdca8-p-arg35gln), [CDCA8 p.Asp120Glu](/variant/cdca8-p-asp120glu).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 3488587). 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.*