Is CDC73 p.Arg330Gln (c.989G>A) pathogenic?

CDC73 p.Arg330Gln (c.989G>A) is classified Conflicting classifications of pathogenicity in CDC73 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-19). AlphaMissense: ambiguous (0.3982); Ultra-rare (popmax 0.0187%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with CDC73 p.Arg330Gln (c.989G>A)?

CDC73 p.Arg330Gln (c.989G>A) is associated with hereditary neoplastic syndrome, hyperparathyroidism 1, hyperparathyroidism 2 with jaw tumors (ClinVar).

How common is CDC73 p.Arg330Gln (c.989G>A) in the general population?

CDC73 p.Arg330Gln (c.989G>A) is ultra-rare (popmax 0.0187%, afr) (gnomAD).

What do computational predictors say about CDC73 p.Arg330Gln (c.989G>A)?

AlphaMissense predicts ambiguous (score 0.3982) — an in-silico prediction, not a clinical call.

CDC73 p.Arg330Gln

c.989G>A · rs149875598 · VCV403894

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.3982 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3982	ambiguous
REVEL	0.355	indeterminate
SaProt	LLR -5.56	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 109 kb · p 8.5e-19 · regional, not allelic
Overall
CADD	24.7	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 0.0187% African / African-American · 14/74,856 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00905%

Overall 0.00849% 137/1,613,196 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0187%	5,347
Remaining individualsnot grpmax-eligible	0.0112%	8,923
European (non-Finnish)	0.0095%	10,530
Finnishnot grpmax-eligible	0.00625%	15,999

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.Arg330Gln
Coding: c.989G>A
MANE Select: NM_024529
dbSNP: rs149875598
Type: single nucleotide variant
Location: chr1:193203811 (GRCh38)
Gene constraint: LOEUF 0.42 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.94 · 21 PDB
Residue 330: 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 hyperparathyroidism 2 with jaw tumors parathyroid gland carcinoma

Similar variants

CDC73 p.Arg330Trp Uncertain significance ★★ ⚠ same residue
CDC73 p.Arg330Gly Uncertain significance ★ ⚠ same residue
CDC73 p.Arg330Leu Uncertain significance ★ ⚠ same residue
CDC73 p.Arg330= 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-arg330gln (accessed [today's date]).

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