# NM_003504.5(CDC45):c.318C>T (p.Val106=)

https://sugi.bio/variant/cdc45-p-val106

## Summary

**CDC45 p.Val106= (c.318C>T)** is classified **Uncertain significance** in CDC45 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-05-31). Ultra-rare (popmax 0.0134%, eas); Associated with Meier-Gorlin syndrome 7.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs745800041 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0134%, eas)

## For patients & families {#patients}

This is a change in the CDC45 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to Meier-Gorlin syndrome 7.

*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/0016181/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CDC45](https://sugi.bio/atlas/gene/CDC45/) |
| Protein change (HGVS p.) | p.Val106= |
| Coding change (HGVS c.) | c.318C>T |
| MANE Select transcript | [NM_003504](https://www.ncbi.nlm.nih.gov/nuccore/NM_003504) |
| dbSNP | [rs745800041](https://www.ncbi.nlm.nih.gov/snp/rs745800041/) |
| Variant type | single nucleotide variant |
| Location | chr22:19482803-19482803 (GRCh38) |
| ClinVar | [VCV253098](https://www.ncbi.nlm.nih.gov/clinvar/variation/253098/) |

**All HGVS expressions:** `NC_000022.10:g.19470326C>T`, `NC_000022.11:g.19482803C>T`, `NG_052958.1:g.7978C>T`, `NM_001178010.2:c.318C>T`, `NM_001178011.2:c.205-1059C>T`, `NM_001369291.1:c.282C>T`, `NM_003504.5:c.318C>T`, `NR_161281.1:n.367C>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.21) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -6.078, GERP -3.31 — fast-evolving / accelerated position
- CADD: **PHRED 0.28**. 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 deltas (raw): acceptor loss **0.09**, donor loss **0.21**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.09**, donor loss **0.21**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.31** (loss), gain 0.00 / loss 0.31. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0134%** (eas) · FAF95 0.00579% · FAF99 0.00394% · 6/44,888 in the highest group · 21/1,613,980 alleles overall — ultra-rare (popmax 0.0134%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0134% | 7,481 |
| Admixed American | 0.00333% | 30,012 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,248 |
| European (non-Finnish) | 0.000932% | 107,260 |

*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}

**CDC45** population constraint: LOEUF 0.77, pLI 6.6732e-08, missense-Z 1.4196. *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 7** — Definitive (AR)

## Protein context {#protein}

Residue **106** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 92.59, 85% of residues very-high.

**7 experimental structure(s)** (PDB): [5DGO](https://www.rcsb.org/structure/5DGO), [6XTX](https://www.rcsb.org/structure/6XTX), [6XTY](https://www.rcsb.org/structure/6XTY), [7PFO](https://www.rcsb.org/structure/7PFO), [7PLO](https://www.rcsb.org/structure/7PLO), [8B9D](https://www.rcsb.org/structure/8B9D).

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

*Describes the biological roles of CDC45 (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}

CDC45 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of ATR in response to replication stress](https://reactome.org/content/detail/R-HSA-176187) | curated |
| [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 |
| [Unwinding of DNA](https://reactome.org/content/detail/R-HSA-176974) | electronic |

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

**Biological process:** DNA replication.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-05-31.

**Submitter consensus:** conflicting (1 Pathogenic, 1 Uncertain significance).

**Submission history:** 2 submissions (2016–2022); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2016-10-20 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-05-31 |

## Associated conditions {#conditions}

[Meier-Gorlin syndrome 7](https://sugi.bio/atlas/disease/meier-gorlin-syndrome-7/).

**Reported phenotype names (ClinVar):** Meier-Gorlin syndrome 7, not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related CDC45 variant pages (same residue, condition, or type): [CDC45 p.Pro463Leu](/variant/cdc45-p-pro463leu), [CDC45 p.Ile509Val](/variant/cdc45-p-ile509val), [CDC45 p.Pro496Leu](/variant/cdc45-p-pro496leu), [CDC45 p.Ala298Val](/variant/cdc45-p-ala298val), [CDC45 p.Asn76His](/variant/cdc45-p-asn76his), [CDC45 p.Asp226Gly](/variant/cdc45-p-asp226gly), [CDC45 p.Gln68Arg](/variant/cdc45-p-gln68arg), [CDC45 p.Glu548Ter](/variant/cdc45-p-glu548ter).

### 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 253098). 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.*