# NM_024529.5(CDC73):c.1045C>A (p.Pro349Thr)

https://sugi.bio/variant/cdc73-p-pro349thr

## Summary

**CDC73 p.Pro349Thr (c.1045C>A)** is classified **Uncertain significance** in CDC73 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-17). AlphaMissense: likely benign (0.2703); Very rare (popmax 8.61e-05%, nfe); Associated with hereditary neoplastic syndrome.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs771975951 · 2 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 8.61e-05%, nfe)

## For patients & families {#patients}

This is a change in the CDC73 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 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.Pro349Thr |
| Coding change (HGVS c.) | c.1045C>A |
| MANE Select transcript | [NM_024529](https://www.ncbi.nlm.nih.gov/nuccore/NM_024529) |
| dbSNP | [rs771975951](https://www.ncbi.nlm.nih.gov/snp/rs771975951/) |
| Variant type | single nucleotide variant |
| Location | chr1:193212079-193212079 (GRCh38) |
| ClinVar | [VCV1996342](https://www.ncbi.nlm.nih.gov/clinvar/variation/1996342/) |

**All HGVS expressions:** `LRG_507:g.95122C>A`, `LRG_507t1:c.1045C>A`, `NC_000001.10:g.193181209C>A`, `NC_000001.11:g.193212079C>A`, `NG_012691.1:g.95122C>A`, `NM_024529.5:c.1045C>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2703)
- REVEL 0.102 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.807 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 5.941, GERP 2.41, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 21.8**. 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 (193,141,907–193,250,709), spanning 108,802 bp. Chi-square p 8.5e-19. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **8.61e-05%** (nfe) · 1/1,160,970 in the highest group · 2/1,433,044 alleles overall — very rare (popmax 8.61e-05%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.0016% | 62,414 |
| European (non-Finnish) (grpmax) | 8.61e-05% | 1,160,970 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

Residue **349** lies in the 'interaction with polr2a and paf1' region; the 'disordered' region.

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. p.Pro349Thr falls in the interaction with polr2a and paf1 region. 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-12-17.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2022–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-12-17 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-05-19 |

## 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, Neoplastic Syndromes, Hereditary, Hereditary neoplastic syndrome, 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.Pro349=](/variant/cdc73-p-pro349), [CDC73 p.Pro349Leu](/variant/cdc73-p-pro349leu), [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), [CDC73 c.513-1G>A](/variant/cdc73-c-513-minus-1g-a), [CDC73 p.Arg120Ter](/variant/cdc73-p-arg120ter).

### 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 1996342). 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.*