Is CDC73 p.Asp379Glu (c.1137C>G) pathogenic?

CDC73 p.Asp379Glu (c.1137C>G) is classified Conflicting classifications of pathogenicity in CDC73 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-03-04). AlphaMissense: ambiguous (0.4951); Very rare (popmax 0.00167%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with CDC73 p.Asp379Glu (c.1137C>G)?

CDC73 p.Asp379Glu (c.1137C>G) is associated with hereditary neoplastic syndrome, hyperparathyroidism 1, parathyroid gland carcinoma (ClinVar).

How common is CDC73 p.Asp379Glu (c.1137C>G) in the general population?

CDC73 p.Asp379Glu (c.1137C>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CDC73 p.Asp379Glu (c.1137C>G)?

AlphaMissense predicts ambiguous (score 0.4951) — an in-silico prediction, not a clinical call.

CDC73 p.Asp379Glu

c.1137C>G · rs774536123 · VCV403889

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.4951 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4951	ambiguous
REVEL	0.194	benign-leaning
SaProt	LLR -6.62	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.81	GERP 2, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 109 kb · p 8.5e-19 · regional, not allelic
Overall
CADD	17.02	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 0.00167% Admixed American · 1/59,868 alleles

Filtering AF 0.00089% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000728%

Overall 0.00113% 18/1,593,968 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,868
European (non-Finnish)	0.00146%	68,413

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.Asp379Glu
Coding: c.1137C>G
MANE Select: NM_024529
dbSNP: rs774536123
Type: single nucleotide variant
Location: chr1:193212460 (GRCh38)
Gene constraint: LOEUF 0.42 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.94 · 21 PDB
Residue 379: the 'interaction with polr2a and paf1' region; a UniProt-annotated variant site (in hrpt2); an α-helix

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.Asp379Asn Uncertain significance ★★ ⚠ same residue
CDC73 p.Asp379His Uncertain significance ★ ⚠ same residue
CDC73 p.Asp379Tyr Uncertain significance ★ ⚠ same residue
CDC73 p.Asp379= 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-asp379glu (accessed [today's date]).

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