Is CDC73 p.Arg504His (c.1511G>A) pathogenic?

CDC73 p.Arg504His (c.1511G>A) is classified Conflicting classifications of pathogenicity in CDC73 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-05). AlphaMissense: likely pathogenic (0.9417); Very rare (popmax 0.000764%, nfe); Associated with parathyroid gland carcinoma.

What condition is associated with CDC73 p.Arg504His (c.1511G>A)?

CDC73 p.Arg504His (c.1511G>A) is associated with parathyroid gland carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is CDC73 p.Arg504His (c.1511G>A) in the general population?

CDC73 p.Arg504His (c.1511G>A) is very rare (popmax 0.000764%, nfe) (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.Arg504His (c.1511G>A)?

AlphaMissense predicts likely pathogenic (score 0.9417) — an in-silico prediction, not a clinical call.

CDC73 p.Arg504His

c.1511G>A · rs759222387 · VCV1433257

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9417 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000764%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

parathyroid gland carcinoma

Computational evidence

Protein change
AlphaMissense	0.9417	likely pathogenic
REVEL	0.904	moderately pathogenic-leaning
SaProt	LLR -12.94	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 109 kb · p 8.5e-19 · regional, not allelic
Overall
CADD	31.0	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 0.000764% European (non-Finnish) · 9/1,178,508 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000685% 10/1,460,206 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	63,966
European (non-Finnish)grpmax	0.000764%	130,945

Finnish shows a higher raw frequency than the grpmax group above it. 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.

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.Arg504His
Coding: c.1511G>A
MANE Select: NM_024529
dbSNP: rs759222387
Type: single nucleotide variant
Location: chr1:193249823 (GRCh38)
Gene constraint: LOEUF 0.42 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.94 · 21 PDB
Residue 504: the 'interaction with polr2a and paf1' 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.Arg504Cys Uncertain significance ★★ ⚠ same residue
CDC73 p.Arg504Leu Uncertain significance ★ ⚠ same residue
CDC73 p.Arg504Pro Uncertain significance ★ ⚠ same residue
CDC73 p.Arg504= 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-arg504his (accessed [today's date]).

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