# NM_024529.5(CDC73):c.201G>A (p.Val67=)

https://sugi.bio/variant/cdc73-p-val67

## Summary

**CDC73 p.Val67= (c.201G>A)** is classified **Conflicting classifications of pathogenicity** in CDC73 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-31). Ultra-rare (popmax 0.0117%, amr); Associated with hyperparathyroidism 1.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs752298916 · 5 submitters · 4 linked conditions · ultra-rare (popmax 0.0117%, amr)

## 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 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.Val67= |
| Coding change (HGVS c.) | c.201G>A |
| MANE Select transcript | [NM_024529](https://www.ncbi.nlm.nih.gov/nuccore/NM_024529) |
| dbSNP | [rs752298916](https://www.ncbi.nlm.nih.gov/snp/rs752298916/) |
| Variant type | single nucleotide variant |
| Location | chr1:193125181-193125181 (GRCh38) |
| ClinVar | [VCV294411](https://www.ncbi.nlm.nih.gov/clinvar/variation/294411/) |

**All HGVS expressions:** `LRG_507:g.8224G>A`, `LRG_507t1:c.201G>A`, `NC_000001.10:g.193094311G>A`, `NC_000001.11:g.193125181G>A`, `NG_012691.1:g.8224G>A`, `NM_024529.5:c.201G>A`

## Computational & population evidence {#evidence}

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

- **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 -0.298, GERP -1.26, phastCons 0.009 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 5.002**. 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.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for CDC73 (1,019 scored positions, the nearest 21 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.0117%** (amr) · FAF95 0.00543% · FAF99 0.0038% · 7/60,004 in the highest group · 43/1,607,966 alleles overall — ultra-rare (popmax 0.0117%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0203% | 4,928 |
| Admixed American (grpmax) | 0.0117% | 8,572 |
| Remaining individuals (not grpmax-eligible) | 0.00482% | 20,762 |
| European (non-Finnish) | 0.0023% | 43,500 |

Ashkenazi Jewish 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 3/3, triplosensitivity 0/3. *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 **67** lies in a turn.

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 2026-01-31.

**Submitter consensus:** conflicting (6 Likely benign, 1 Uncertain significance).

**Submission history:** 7 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2019-04-09 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-31 |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2024-05-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-10-28 |

## Associated conditions {#conditions}

[hyperparathyroidism 1](https://sugi.bio/atlas/disease/hyperparathyroidism-1/), [hyperparathyroidism 2 with jaw tumors](https://sugi.bio/atlas/disease/hyperparathyroidism-2-with-jaw-tumors/), [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, Hyperparathyroidism 2 with jaw tumors, Parathyroid carcinoma, Hereditary cancer-predisposing syndrome, not provided, not specified, HYPERPARATHYROIDISM, FAMILIAL ISOLATED PRIMARY, Hereditary neoplastic syndrome, Tumor predisposition, Hereditary Cancer Syndrome.

## Similar variants {#similar}

Related CDC73 variant pages (same residue, condition, or type): [CDC73 p.Val67Met](/variant/cdc73-p-val67met), [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), [CDC73 p.Arg126Ter](/variant/cdc73-p-arg126ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2026-10-14); 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 294411). 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.*