# NM_030928.4(CDT1):c.162_163insTCCC (p.Ala55fs)

https://sugi.bio/variant/cdt1-p-ala55fs

## Summary

**CDT1 p.Ala55fs (c.162_163insTCCC)** is classified **Likely pathogenic** in CDT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-20). Associated with Meier-Gorlin syndrome 4.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the CDT1 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to Meier-Gorlin syndrome 4.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015711/index) · [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.Ala55fs |
| Coding change (HGVS c.) | c.162_163insTCCC |
| MANE Select transcript | [NM_030928](https://www.ncbi.nlm.nih.gov/nuccore/NM_030928) |
| Variant type | Insertion |
| Location | chr16:88803990-88803991 (GRCh38) |
| ClinVar | [VCV4849302](https://www.ncbi.nlm.nih.gov/clinvar/variation/4849302/) |

**All HGVS expressions:** `NC_000016.10:g.88803993_88803994insTCCC`, `NC_000016.9:g.88870401_88870402insTCCC`, `NG_028266.1:g.5216_5217insTCCC`, `NG_194180.1:g.223_224insTCCC`, `NM_030928.4:c.162_163insTCCC`

## 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 -0.355, GERP -1.9 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.737, pLI 1.2251e-28. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 1 of 10**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no insertion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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 gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *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}

Residue **55** lies in the 'disordered' region.

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. p.Ala55fs falls in the disordered region.


### 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}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-06-20.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| First Genomix Gene Laboratory, Genetic Diagnostics Department | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-06-20 |

## Associated conditions {#conditions}

[Meier-Gorlin syndrome 4](https://sugi.bio/atlas/disease/meier-gorlin-syndrome-4/).

**Reported phenotype names (ClinVar):** Meier-Gorlin syndrome 4.

## Similar variants {#similar}

Related CDT1 variant pages (same residue, condition, or type): [CDT1 c.832+1G>A](/variant/cdt1-c-832-plus-1g-a), [CDT1 p.Arg462Gln](/variant/cdt1-p-arg462gln), [CDT1 p.Arg250Cys](/variant/cdt1-p-arg250cys), [CDT1 p.Gly281Arg](/variant/cdt1-p-gly281arg), [CDT1 p.Val204Met](/variant/cdt1-p-val204met), [CDT1 p.Cys234Arg](/variant/cdt1-p-cys234arg), [CDT1 p.His305=](/variant/cdt1-p-his305), [CDT1 p.Leu529=](/variant/cdt1-p-leu529).

### 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 4849302). 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.*