Is CDC73 p.Arg513Gln (c.1538G>A) pathogenic?

CDC73 p.Arg513Gln (c.1538G>A) is classified Uncertain significance in CDC73 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-11-18). AlphaMissense: likely benign (0.1244); Very rare (popmax 0.00492%, nfe); Associated with hyperparathyroidism 1.

What condition is associated with CDC73 p.Arg513Gln (c.1538G>A)?

CDC73 p.Arg513Gln (c.1538G>A) is associated with hyperparathyroidism 1, parathyroid gland carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is CDC73 p.Arg513Gln (c.1538G>A) in the general population?

CDC73 p.Arg513Gln (c.1538G>A) is very rare (popmax 0.00492%, nfe) (gnomAD).

How is Familial isolated hyperparathyroidism inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CDC73 p.Arg513Gln (c.1538G>A)?

AlphaMissense predicts likely benign (score 0.1244) — an in-silico prediction, not a clinical call.

CDC73 p.Arg513Gln

c.1538G>A · rs1465509067 · VCV462751

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1244 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00492%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperparathyroidism 1

Computational evidence

Protein change
AlphaMissense	0.1244	likely benign
REVEL	0.189	benign-leaning
SaProt	LLR -7.44	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 109 kb · p 8.5e-19 · regional, not allelic
Overall
CADD	23.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00492% European (non-Finnish) · 58/1,178,758 alleles

Filtering AF 0.00386% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00353%

Overall 0.00404% 59/1,460,472 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00492%	20,323
South Asian	0.0011%	91,038

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.Arg513Gln
Coding: c.1538G>A
MANE Select: NM_024529
dbSNP: rs1465509067
Type: single nucleotide variant
Location: chr1:193249850 (GRCh38)
Gene constraint: LOEUF 0.42 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.94 · 21 PDB
Residue 513: the 'interaction with polr2a and paf1' region; an α-helix

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

Disease context

hyperparathyroidism 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: parathyroid gland carcinoma hereditary neoplastic syndrome

For Familial isolated hyperparathyroidism (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

CDC73 p.Arg513Trp Uncertain significance ★★ ⚠ same residue
CDC73 p.Arg513= 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
CDC73 c.513-1G>A Likely pathogenic ★★ same condition
CDC73 p.Arg120Ter 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-arg513gln (accessed [today's date]).

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