# NM_080668.4(CDCA5):c.315A>G (p.Thr105=)

https://sugi.bio/variant/cdca5-p-thr105

## Summary

**CDCA5 p.Thr105= (c.315A>G)** is classified **Benign** in CDCA5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-08-17). Low-frequency (popmax 3.2%, afr).

**At a glance:** Benign · review: Multiple submitters · rsID rs35616304 · 2 submitters · low-frequency (popmax 3.2%, afr)

## For patients & families {#patients}

This is a change in the CDCA5 gene that is classified as benign — not considered disease-causing, submitted by 2 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 | [CDCA5](https://sugi.bio/atlas/gene/CDCA5/) |
| Protein change (HGVS p.) | p.Thr105= |
| Coding change (HGVS c.) | c.315A>G |
| MANE Select transcript | [NM_080668](https://www.ncbi.nlm.nih.gov/nuccore/NM_080668) |
| dbSNP | [rs35616304](https://www.ncbi.nlm.nih.gov/snp/rs35616304/) |
| Variant type | single nucleotide variant |
| Location | chr11:65079716-65079716 (GRCh38) |
| ClinVar | [VCV716423](https://www.ncbi.nlm.nih.gov/clinvar/variation/716423/) |

**All HGVS expressions:** `NC_000011.10:g.65079716T>C`, `NC_000011.9:g.64847188T>C`, `NM_080668.4:c.315A>G`

## 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 -2.611, GERP -4.66 — fast-evolving / accelerated position
- CADD: **PHRED 0.176**. 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 (T>A, Δ0.47 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 **3.2%** (afr) · FAF95 3.09% · FAF99 3.05% · 2,313/72,222 in the highest group · 2,716/1,542,330 alleles overall — low-frequency (popmax 3.2%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 3.2% | 31 |
| Admixed American | 0.272% | 368 |
| Remaining individuals (not grpmax-eligible) | 0.235% | 426 |
| Middle Eastern | 0.0348% | 2,873 |
| European (non-Finnish) | 0.0115% | 8,677 |
| South Asian | 0.00246% | 40,730 |
| East Asian | 0.0023% | 43,470 |

*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}

**CDCA5** population constraint: LOEUF 0.88, pLI 0.0041618, missense-Z 0.19315. *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 **105** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 63.04, 4% of residues very-high.

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

*Describes the biological roles of CDCA5 (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:** CDCA5's established molecular role includes protein-containing complex binding. p.Thr105= falls in the disordered region.


### Pathways affected {#pathways}

CDCA5 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Establishment of Sister Chromatid Cohesion](https://reactome.org/content/detail/R-HSA-2468052) | curated |
| [Resolution of Sister Chromatid Cohesion](https://reactome.org/content/detail/R-HSA-2500257) | curated |
| [Separation of Sister Chromatids](https://reactome.org/content/detail/R-HSA-2467813) | curated |

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

**Molecular function:** protein-containing complex binding.

**Biological process:** double-strand break repair, mitotic sister chromatid cohesion.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2018-08-17.

**Submitter consensus:** unanimous (2/2 Benign).

**Submission history:** 2 submissions (2018); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2018-08-17 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related CDCA5 variant pages (same residue, condition, or type): [CDCA5 p.Glu123Lys](/variant/cdca5-p-glu123lys), [CDCA5 p.Gly173=](/variant/cdca5-p-gly173), [CDCA5 p.Gly179Arg](/variant/cdca5-p-gly179arg), [CDCA5 p.Pro120=](/variant/cdca5-p-pro120), [CDCA5 p.Ala51Thr](/variant/cdca5-p-ala51thr), [CDCA5 p.Arg148Trp](/variant/cdca5-p-arg148trp), [CDCA5 p.Arg4Gly](/variant/cdca5-p-arg4gly), [CDCA5 p.Arg4Lys](/variant/cdca5-p-arg4lys).

### 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 716423). 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.*