# NM_030928.4(CDT1):c.696G>C (p.Glu232Asp)

https://sugi.bio/variant/cdt1-p-glu232asp

## Summary

**CDT1 p.Glu232Asp (c.696G>C)** is classified **Uncertain significance** in CDT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-22). AlphaMissense: likely benign (0.2821); Ultra-rare (popmax 0.0107%, afr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0107%, afr)

## For patients & families {#patients}

This is a change in the CDT1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [CDT1](https://sugi.bio/atlas/gene/CDT1/) |
| Protein change (HGVS p.) | p.Glu232Asp |
| Coding change (HGVS c.) | c.696G>C |
| MANE Select transcript | [NM_030928](https://www.ncbi.nlm.nih.gov/nuccore/NM_030928) |
| Variant type | single nucleotide variant |
| Location | chr16:88805733-88805733 (GRCh38) |
| ClinVar | [VCV4610620](https://www.ncbi.nlm.nih.gov/clinvar/variation/4610620/) |

**All HGVS expressions:** `NC_000016.10:g.88805733G>C`, `NC_000016.9:g.88872141G>C`, `NG_028266.1:g.6956G>C`, `NG_134888.1:g.613G>C`, `NM_030928.4:c.696G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2821)
- REVEL 0.189 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.146 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor gain** (Δ 0.43) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 2.504, GERP 0.243, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 22.0**. 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 1.19** across the covering region of the MANE Select transcript (88,803,832–88,808,275), spanning 4,443 bp. Chi-square p 1.2e-07. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.06**, donor loss **0.00**, acceptor gain **0.43**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.43**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0107%** (afr) · FAF95 0.00528% · FAF99 0.00381% · 8/74,938 in the highest group · 9/1,612,878 alleles overall — ultra-rare (popmax 0.0107%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0107% | 9,367 |
| Admixed American | 0.00167% | 60,004 |

*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}

**CDT1** population constraint: LOEUF 1.737, pLI 1.2251e-28, missense-Z -2.6749; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (0–3 scale). *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):

- **Meier-Gorlin syndrome 4** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 74.51, 35% of residues very-high.

**6 experimental structure(s)** (PDB): [2LE8](https://www.rcsb.org/structure/2LE8), [2WVR](https://www.rcsb.org/structure/2WVR), [6QCG](https://www.rcsb.org/structure/6QCG), [8RWV](https://www.rcsb.org/structure/8RWV), [8S0E](https://www.rcsb.org/structure/8S0E), [8S0F](https://www.rcsb.org/structure/8S0F).

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

*Describes the biological roles of CDT1 (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:** CDT1's established molecular role includes chromatin binding.


### Pathways affected {#pathways}

CDT1 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of the pre-replicative complex](https://reactome.org/content/detail/R-HSA-68962) | curated |
| [G1/S-Specific Transcription](https://reactome.org/content/detail/R-HSA-69205) | curated |
| [Orc1 removal from chromatin](https://reactome.org/content/detail/R-HSA-68949) | curated |
| [Switching of origins to a post-replicative state](https://reactome.org/content/detail/R-HSA-69052) | curated |
| [Assembly of the pre-replicative complex](https://reactome.org/content/detail/R-HSA-68867) | electronic |

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

**Molecular function:** chromatin binding.

**Biological process:** DNA replication checkpoint signaling, positive regulation of DNA replication, negative regulation of cell cycle, attachment of mitotic spindle microtubules to kinetochore, response to sorbitol, mitotic DNA replication initiation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-10-22.

**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 | 2025-10-22 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related CDT1 variant pages (same residue, condition, or type): [CDT1 p.Ala11Val](/variant/cdt1-p-ala11val), [CDT1 p.Ala144Ser](/variant/cdt1-p-ala144ser), [CDT1 p.Ala167Thr](/variant/cdt1-p-ala167thr), [CDT1 p.Ala217Val](/variant/cdt1-p-ala217val), [CDT1 p.Ala414Ser](/variant/cdt1-p-ala414ser), [CDT1 p.Ala431Thr](/variant/cdt1-p-ala431thr), [CDT1 p.Ala534Val](/variant/cdt1-p-ala534val), [CDT1 p.Ala90Thr](/variant/cdt1-p-ala90thr).

### 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 4610620). 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.*