# NM_024529.5(CDC73):c.687_688del (p.Arg229fs)

https://sugi.bio/variant/cdc73-p-arg229fs

## Summary

**CDC73 p.Arg229fs (c.687_688del)** is classified **Pathogenic** in CDC73 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-12). No allele count reported in gnomAD v4.1 (AN 1,613,454); Associated with parathyroid gland carcinoma.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs760591174 · 2 submitters · 2 linked conditions · no allele count reported in gnomAD v4.1 (AN 1,613,454)

## For patients & families {#patients}

This is a change in the CDC73 gene that is considered disease-causing, submitted by 2 submitters, and is linked to parathyroid gland carcinoma.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Not applicable |
| Age of onset (of this condition) | Adult |
| Prevalence | <1 / 1 000 000 (Europe) |
| Clinical trials | 30 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CDC73 is a diagnostic-grade gene on 8 Genomics England panels |

**Commonly reported features of Parathyroid carcinoma** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hypercalcemia — Obligate (100%)
- Parathyroid carcinoma — Obligate (100%)
- Primary hyperparathyroidism — Obligate (100%)
- Hypophosphatemia — Very frequent (99-80%)
- Hypercalciuria — Very frequent (99-80%)
- Elevated circulating parathyroid hormone level — Very frequent (99-80%)
- Abnormality of the parathyroid morphology — Very frequent (99-80%)
- Nephrocalcinosis — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007329/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.Arg229fs |
| Coding change (HGVS c.) | c.687_688del |
| MANE Select transcript | [NM_024529](https://www.ncbi.nlm.nih.gov/nuccore/NM_024529) |
| dbSNP | [rs760591174](https://www.ncbi.nlm.nih.gov/snp/rs760591174/) |
| Variant type | Microsatellite |
| Location | chr1:193142016-193142017 (GRCh38) |
| ClinVar | [VCV1076788](https://www.ncbi.nlm.nih.gov/clinvar/variation/1076788/) |

**All HGVS expressions:** `LRG_507:g.25059AG[4]`, `NC_000001.10:g.193111146AG[4]`, `NC_000001.11:g.193142016AG[4]`, `NG_012691.1:g.25059AG[4]`, `NM_024529.5:c.687_688del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 2.651, GERP 1.17, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.42, pLI 0.99901), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 7 of 17**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,613,454)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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 **229** lies in the 'interaction with polr2a and paf1' region; the 'interaction with ctnnb1' 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.Arg229fs 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}

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

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2021–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| MGZ Medical Genetics Center | Pathogenic | criteria provided, single submitter | clinical testing | 2021-11-22 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-12-12 |

## Associated conditions {#conditions}

[parathyroid gland carcinoma](https://sugi.bio/atlas/disease/parathyroid-gland-carcinoma/), [hyperparathyroidism 2 with jaw tumors](https://sugi.bio/atlas/disease/hyperparathyroidism-2-with-jaw-tumors/).

**Reported phenotype names (ClinVar):** Parathyroid carcinoma, Hyperparathyroidism 2 with jaw tumors, Parathyroid gland carcinoma, CDC73-Related Parathyroid Carcinoma, Hyperparathyroidism 2, HYPERPARATHYROIDISM, FAMILIAL PRIMARY, WITH MULTIPLE OSSIFYING JAW FIBROMAS, HYPERPARATHYROIDISM-JAW TUMOR SYNDROME, HEREDITARY, Hyperparathyroidism-Jaw Tumor Syndrome.

## Same-residue context {#hotspot}

Residue **229** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CDC73 p.Arg229Ter](/variant/cdc73-p-arg229ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CDC73 variant pages (same residue, condition, or type): [CDC73 p.Arg229Ser](/variant/cdc73-p-arg229ser), [CDC73 p.Arg229=](/variant/cdc73-p-arg229), [CDC73 p.Arg229Ter](/variant/cdc73-p-arg229ter), [CDC73 p.His160fs](/variant/cdc73-p-his160fs), [CDC73 p.Val230fs](/variant/cdc73-p-val230fs), [CDC73 p.Asn66del](/variant/cdc73-p-asn66del), [CDC73 p.Glu261del](/variant/cdc73-p-glu261del), [CDC73 p.Lys394del](/variant/cdc73-p-lys394del).

### 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 1076788). 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.*