# NM_024529.5(CDC73):c.305C>T (p.Ala102Val)

https://sugi.bio/variant/cdc73-p-ala102val

## Summary

**CDC73 p.Ala102Val (c.305C>T)** is classified **Conflicting classifications of pathogenicity** in CDC73 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-02-13). AlphaMissense: likely benign (0.0766); Very rare (popmax 0.00446%, sas); Associated with hereditary neoplastic syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs778134705 · 3 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00446%, sas)

## For patients & families {#patients}

This is a change in the CDC73 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to hereditary neoplastic syndrome.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 31 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019921/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CDC73](https://sugi.bio/atlas/gene/CDC73/) |
| Protein change (HGVS p.) | p.Ala102Val |
| Coding change (HGVS c.) | c.305C>T |
| MANE Select transcript | [NM_024529](https://www.ncbi.nlm.nih.gov/nuccore/NM_024529) |
| dbSNP | [rs778134705](https://www.ncbi.nlm.nih.gov/snp/rs778134705/) |
| Variant type | single nucleotide variant |
| Location | chr1:193130241-193130241 (GRCh38) |
| ClinVar | [VCV1507593](https://www.ncbi.nlm.nih.gov/clinvar/variation/1507593/) |

**All HGVS expressions:** `LRG_507:g.13284C>T`, `LRG_507t1:c.305C>T`, `NC_000001.10:g.193099371C>T`, `NC_000001.11:g.193130241C>T`, `NG_012691.1:g.13284C>T`, `NM_024529.5:c.305C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0766)
- REVEL 0.308 (indeterminate)
- SaProt LLR -3.655 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 7.619, GERP 1.93, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.3**. 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 0.57** across the covering region of the MANE Select transcript (193,122,201–193,138,088), spanning 15,887 bp. Chi-square p 1.1e-08. 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, Δ0.61 donor 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 **0.00446%** (sas) · FAF95 0.00144% · FAF99 0.000902% · 4/89,662 in the highest group · 21/1,542,368 alleles overall — very rare (popmax 0.00446%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00446% | 22,415 |
| Admixed American | 0.00334% | 29,960 |
| Remaining individuals (not grpmax-eligible) | 0.00166% | 60,102 |
| European (non-Finnish) | 0.00126% | 79,672 |

*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}

**CDC73** population constraint: LOEUF 0.42, pLI 0.99901, missense-Z 3.3697; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (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):

- **hyperparathyroidism 2 with jaw tumors** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 73.94, 27% of residues very-high.

**21 experimental structure(s)** (PDB): [5YDE](https://www.rcsb.org/structure/5YDE), [5YDF](https://www.rcsb.org/structure/5YDF), [6TED](https://www.rcsb.org/structure/6TED), [7OOP](https://www.rcsb.org/structure/7OOP), [7OPC](https://www.rcsb.org/structure/7OPC), [7OPD](https://www.rcsb.org/structure/7OPD).

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

*Describes the biological roles of CDC73 (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:** CDC73's established molecular role includes RNA polymerase II complex binding. In Reactome, CDC73 is annotated in disease pathway(s) including **Dengue virus activates/modulates innate and adaptive immune responses**.

**Disease mechanism (Reactome):** CDC73 loss or alteration is curated in [Dengue virus activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9920588).

### Pathways affected {#pathways}

CDC73 participates in **9 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Dengue virus activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9920588) | curated |
| [CHD1 and CHD2 subfamily](https://reactome.org/content/detail/R-HSA-9943411) | curated |
| [E3 ubiquitin ligases ubiquitinate target proteins](https://reactome.org/content/detail/R-HSA-8866654) | curated |
| [Formation of RNA Pol II elongation complex ](https://reactome.org/content/detail/R-HSA-112382) | curated |
| [Formation of the beta-catenin:TCF transactivating complex](https://reactome.org/content/detail/R-HSA-201722) | curated |
| [Hedgehog 'on' state](https://reactome.org/content/detail/R-HSA-5632684) | curated |
| [RNA Polymerase II Pre-transcription Events](https://reactome.org/content/detail/R-HSA-674695) | curated |
| [RNA Polymerase II Transcription Elongation](https://reactome.org/content/detail/R-HSA-75955) | curated |
| [Somatic hypermutation of immunoglobulin genes](https://reactome.org/content/detail/R-HSA-9938024) | electronic |

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

**Molecular function:** RNA polymerase II complex binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, transcription elongation by RNA polymerase II, negative regulation of cell population proliferation, positive regulation of Wnt signaling pathway, mRNA 3'-end processing, positive regulation of mRNA 3'-end processing.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-02-13.

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

**Submission history:** 3 submissions (2023–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-10-10 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-02-13 |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [parathyroid gland carcinoma](https://sugi.bio/atlas/disease/parathyroid-gland-carcinoma/).

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, Parathyroid carcinoma, Ovarian serous cystadenocarcinoma, Hereditary neoplastic syndrome, Neoplastic Syndromes, Hereditary, Tumor predisposition, Hereditary Cancer Syndrome, Parathyroid gland carcinoma, CDC73-Related Parathyroid Carcinoma.

## Similar variants {#similar}

Related CDC73 variant pages (same residue, condition, or type): [CDC73 p.Ala102Gly](/variant/cdc73-p-ala102gly), [CDC73 p.Ala102Ser](/variant/cdc73-p-ala102ser), [CDC73 p.Ala102Thr](/variant/cdc73-p-ala102thr), [CDC73 p.Ala102=](/variant/cdc73-p-ala102), [CDC73 c.1030+2T>C](/variant/cdc73-c-1030-plus-2t-c), [CDC73 c.131+1G>A](/variant/cdc73-c-131-plus-1g-a), [CDC73 c.237+1G>A](/variant/cdc73-c-237-plus-1g-a), [CDC73 c.423+1G>A](/variant/cdc73-c-423-plus-1g-a).

### 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 1507593). 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.*