Is CDC73 p.Val230fs (c.687_688dup) pathogenic?

CDC73 p.Val230fs (c.687688dup) is classified Pathogenic in CDC73 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-09-24). Very rare (popmax 0.00017%, nfe); Associated with CDC73-related disorder.

What condition is associated with CDC73 p.Val230fs (c.687_688dup)?

CDC73 p.Val230fs (c.687_688dup) is associated with CDC73-related disorder, hyperparathyroidism 1, hyperparathyroidism 2 with jaw tumors (ClinVar).

How common is CDC73 p.Val230fs (c.687_688dup) in the general population?

CDC73 p.Val230fs (c.687_688dup) is very rare (popmax 0.00017%, nfe) (gnomAD).

CDC73 p.Val230fs

c.687_688dup · rs760591174 · VCV241496

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

CDC73-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 7 of 17
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.7	GERP 1.2, phastCons 1
Overall
CADD	29.9	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,794 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,348 alleles · very rare

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.Val230fs
Coding: c.687_688dup
MANE Select: NM_024529
dbSNP: rs760591174
Type: Microsatellite
Location: chr1:193142015 (GRCh38)
Gene constraint: LOEUF 0.42 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.94 · 21 PDB
Residue 230: the 'interaction with polr2a and paf1' region; the 'interaction with ctnnb1' region

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

Disease context

Also linked: hyperparathyroidism 1 hyperparathyroidism 2 with jaw tumors parathyroid gland carcinoma hereditary neoplastic syndrome

Similar variants

CDC73 p.Val230Ile Uncertain significance ★★ ⚠ same residue
CDC73 p.Val230= Likely benign ★★ same residue
CDC73 p.Val230Ala Uncertain significance ★ ⚠ same residue
CDC73 p.Val230Glu Uncertain significance ★ ⚠ same residue
CDC73 p.Arg229fs Pathogenic ★★ same condition
CDC73 p.His160fs Pathogenic/Likely pathogenic ★★ same condition
CDC73 p.Asn66del Uncertain significance ★★ same condition
CDC73 p.Glu261del Uncertain significance ★★ 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-val230fs (accessed [today's date]).

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