Is CDC73 p.Pro335Arg (c.1004C>G) pathogenic?

CDC73 p.Pro335Arg (c.1004C>G) is classified Uncertain significance in CDC73 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-27). AlphaMissense: ambiguous (0.5225); Very rare (popmax 0.00134%, afr); Associated with parathyroid gland carcinoma.

What condition is associated with CDC73 p.Pro335Arg (c.1004C>G)?

CDC73 p.Pro335Arg (c.1004C>G) is associated with parathyroid gland carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is CDC73 p.Pro335Arg (c.1004C>G) in the general population?

CDC73 p.Pro335Arg (c.1004C>G) is very rare (popmax 0.00134%, afr) (gnomAD).

How is Parathyroid carcinoma inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CDC73 p.Pro335Arg (c.1004C>G)?

AlphaMissense predicts ambiguous (score 0.5225) — an in-silico prediction, not a clinical call.

CDC73 p.Pro335Arg

c.1004C>G · rs1476163101 · VCV652321

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5225 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

parathyroid gland carcinoma

Computational evidence

Protein change
AlphaMissense	0.5225	ambiguous
REVEL	0.45	indeterminate
SaProt	LLR -8.98	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 109 kb · p 8.5e-19 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,894 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000496% 8/1,613,720 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,894
European (non-Finnish)	0.000593%	168,547

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CDC73
Protein: p.Pro335Arg
Coding: c.1004C>G
MANE Select: NM_024529
dbSNP: rs1476163101
Type: single nucleotide variant
Location: chr1:193203826 (GRCh38)
Gene constraint: LOEUF 0.42 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.94 · 21 PDB
Residue 335: the 'interaction with polr2a and paf1' region; the 'disordered' region

Full CDC73 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

parathyroid gland carcinoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Parathyroid carcinoma (Orphanet):

Inheritance: Not applicable
Onset: Adult
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

CDC73 p.Pro335Ser Uncertain significance ★★ ⚠ same residue
CDC73 p.Pro335Leu Uncertain significance ★ ⚠ same residue
CDC73 p.Pro335Thr Uncertain significance ★ ⚠ same residue
CDC73 p.Pro335= Likely benign ★ same residue
CDC73 c.1030+2T>C Likely pathogenic ★★ same condition
CDC73 c.131+1G>A Pathogenic/Likely pathogenic ★★ same condition
CDC73 c.237+1G>A Pathogenic ★★ same condition
CDC73 c.423+1G>A Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cdc73-p-pro335arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown