# NM_003504.5(CDC45):c.520C>T (p.Arg174Trp)

https://sugi.bio/variant/cdc45-p-arg174trp

## Summary

**CDC45 p.Arg174Trp (c.520C>T)** is classified **Conflicting classifications of pathogenicity** in CDC45 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-29). AlphaMissense: likely benign (0.1321); Rare (popmax 0.202%, amr).

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs184924520 · 2 submitters · AlphaMissense likely benign · rare (popmax 0.202%, amr)

## For patients & families {#patients}

This is a change in the CDC45 gene that is of uncertain or conflicting significance (submitters disagree on it), 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 | [CDC45](https://sugi.bio/atlas/gene/CDC45/) |
| Protein change (HGVS p.) | p.Arg174Trp |
| Coding change (HGVS c.) | c.520C>T |
| MANE Select transcript | [NM_003504](https://www.ncbi.nlm.nih.gov/nuccore/NM_003504) |
| dbSNP | [rs184924520](https://www.ncbi.nlm.nih.gov/snp/rs184924520/) |
| Variant type | single nucleotide variant |
| Location | chr22:19494360-19494360 (GRCh38) |
| ClinVar | [VCV1003669](https://www.ncbi.nlm.nih.gov/clinvar/variation/1003669/) |

**All HGVS expressions:** `NC_000022.10:g.19481883C>T`, `NC_000022.11:g.19494360C>T`, `NG_052958.1:g.19535C>T`, `NM_001178010.2:c.520C>T`, `NM_001178011.2:c.382C>T`, `NM_001369291.1:c.484C>T`, `NM_003504.5:c.520C>T`, `NR_161281.1:n.569C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1321)
- REVEL 0.214 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -11.477 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense and REVEL do not
- Conservation: phyloP 1.796, GERP -0.4, phastCons 1 — weakly conserved position
- CADD: **PHRED 23.5**. 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 0.90** across the covering region of the MANE Select transcript (19,479,969–19,518,905), spanning 38,936 bp. Chi-square p 0.0069. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.40 donor loss), 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 **0.202%** (amr) · FAF95 0.172% · FAF99 0.161% · 121/60,008 in the highest group · 139/1,613,252 alleles overall — rare (popmax 0.202%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.202% | 496 |
| East Asian | 0.00668% | 14,962 |
| Remaining individuals (not grpmax-eligible) | 0.00641% | 15,605 |
| South Asian | 0.0022% | 45,513 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,026 |
| African / African-American | 0.00133% | 74,998 |
| European (non-Finnish) | 0.000593% | 168,568 |

*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 **174** 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-08-29.

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

**Submission history:** 2 submissions (2024–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-09-30 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-08-29 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related CDC45 variant pages (same residue, condition, or type): [CDC45 p.Pro463Leu](/variant/cdc45-p-pro463leu), [CDC45 c.653+4C>T](/variant/cdc45-c-653-plus-4c-t), [CDC45 p.Ala373Val](/variant/cdc45-p-ala373val), [CDC45 p.Ala38Asp](/variant/cdc45-p-ala38asp), [CDC45 p.Arg157His](/variant/cdc45-p-arg157his), [CDC45 p.Arg175Gln](/variant/cdc45-p-arg175gln), [CDC45 p.Arg251His](/variant/cdc45-p-arg251his), [CDC45 p.Arg269Trp](/variant/cdc45-p-arg269trp).

### 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 1003669). 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.*