# NM_024529.5(CDC73):c.842G>A (p.Arg281His)

https://sugi.bio/variant/cdc73-p-arg281his

## Summary

**CDC73 p.Arg281His (c.842G>A)** is classified **Uncertain significance** in CDC73 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-20). AlphaMissense: likely benign (0.1449); Very rare (popmax 0.005%, amr); Associated with hyperparathyroidism 1.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs762716583 · 5 submitters · 3 linked conditions · AlphaMissense likely benign · very rare (popmax 0.005%, amr)

## 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 5 submitters, and is linked to hyperparathyroidism 1.

*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) | Autosomal dominant |
| Age of onset (of this condition) | Adult |
| Diagnostic panels | CDC73 is a diagnostic-grade gene on 8 Genomics England panels |

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

- Nephrocalcinosis — Very frequent (99-80%)
- Chondrocalcinosis — Very frequent (99-80%)
- Osteopenia — Very frequent (99-80%)
- Hypophosphatemia — Very frequent (99-80%)
- Hypercalciuria — Very frequent (99-80%)
- Parathyroid adenoma — Very frequent (99-80%)
- Hypercalcemia — Very frequent (99-80%)
- Hyperphosphaturia — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018253/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.Arg281His |
| Coding change (HGVS c.) | c.842G>A |
| MANE Select transcript | [NM_024529](https://www.ncbi.nlm.nih.gov/nuccore/NM_024529) |
| dbSNP | [rs762716583](https://www.ncbi.nlm.nih.gov/snp/rs762716583/) |
| Variant type | single nucleotide variant |
| Location | chr1:193150317-193150317 (GRCh38) |
| ClinVar | [VCV950136](https://www.ncbi.nlm.nih.gov/clinvar/variation/950136/) |

**All HGVS expressions:** `LRG_507:g.33360G>A`, `LRG_507t1:c.842G>A`, `NC_000001.10:g.193119447G>A`, `NC_000001.11:g.193150317G>A`, `NG_012691.1:g.33360G>A`, `NM_024529.5:c.842G>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** (0.1449)
- REVEL 0.192 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.622 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 11.866, GERP 1.63, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 25.2**. 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 **0.005%** (amr) · FAF95 0.00133% · FAF99 0.000668% · 3/59,978 in the highest group · 17/1,609,942 alleles overall — very rare (popmax 0.005%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.005% | 19,993 |
| Finnish (not grpmax-eligible) | 0.00156% | 63,992 |
| European (non-Finnish) | 0.00111% | 90,489 |

*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 **281** 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.Arg281His 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 2026-01-20.

**Submitter consensus:** unanimous (5/5 Uncertain significance).

**Submission history:** 5 submissions (2021–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-01-20 |
| Sema4, Sema4 | Uncertain significance | criteria provided, single submitter | curation | 2021-09-23 |
| Genetic Services Laboratory, University of Chicago | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-05-26 |
| Baylor Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-08-17 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-02-14 |

## Associated conditions {#conditions}

[hyperparathyroidism 1](https://sugi.bio/atlas/disease/hyperparathyroidism-1/), [parathyroid gland carcinoma](https://sugi.bio/atlas/disease/parathyroid-gland-carcinoma/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** Hyperparathyroidism 1, Parathyroid carcinoma, not specified, Hereditary cancer-predisposing syndrome, AllHighlyPenetrant, HYPERPARATHYROIDISM, FAMILIAL ISOLATED PRIMARY, Tumor predisposition, Hereditary neoplastic syndrome, Neoplastic Syndromes, Hereditary, Hereditary Cancer Syndrome.

## Similar variants {#similar}

Related CDC73 variant pages (same residue, condition, or type): [CDC73 p.Arg281Leu](/variant/cdc73-p-arg281leu), [CDC73 p.Arg281Cys](/variant/cdc73-p-arg281cys), [CDC73 p.Arg281Ser](/variant/cdc73-p-arg281ser), [CDC73 p.Arg281=](/variant/cdc73-p-arg281), [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 950136). 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.*