Is CDC73 p.Arg263Cys (c.787C>T) pathogenic?

CDC73 p.Arg263Cys (c.787C>T) is classified Uncertain significance in CDC73 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-05-13). AlphaMissense: ambiguous (0.5528); Very rare (popmax 0.00267%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with CDC73 p.Arg263Cys (c.787C>T)?

CDC73 p.Arg263Cys (c.787C>T) is associated with hereditary neoplastic syndrome, hyperparathyroidism 1, parathyroid gland carcinoma (ClinVar).

How common is CDC73 p.Arg263Cys (c.787C>T) in the general population?

CDC73 p.Arg263Cys (c.787C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CDC73 p.Arg263Cys (c.787C>T)?

AlphaMissense predicts ambiguous (score 0.5528) — an in-silico prediction, not a clinical call.

CDC73 p.Arg263Cys

c.787C>T · rs878855091 · VCV241497

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.5528 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.5528	ambiguous
REVEL	0.454	indeterminate
SaProt	LLR -13.34	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.8, 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 0.00267% African / African-American · 2/74,912 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000744% 12/1,613,276 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,456
South Asian	0.0022%	45,528
European (non-Finnish)	0.000678%	147,425

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.Arg263Cys
Coding: c.787C>T
MANE Select: NM_024529
dbSNP: rs878855091
Type: single nucleotide variant
Location: chr1:193147924 (GRCh38)
Gene constraint: LOEUF 0.42 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.94 · 21 PDB
Residue 263: 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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hyperparathyroidism 1 parathyroid gland carcinoma

Similar variants

CDC73 p.Arg263His Uncertain significance ★★ ⚠ same residue
CDC73 p.Arg263= Likely benign ★★ same residue
CDC73 p.Arg263Leu Uncertain significance ★ 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

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-arg263cys (accessed [today's date]).

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