Is CDC73 p.Arg358Pro (c.1073G>C) pathogenic?

CDC73 p.Arg358Pro (c.1073G>C) is classified Uncertain significance in CDC73 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-01). AlphaMissense: likely pathogenic (0.9917); Very rare (popmax 8.57e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CDC73 p.Arg358Pro (c.1073G>C)?

CDC73 p.Arg358Pro (c.1073G>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is CDC73 p.Arg358Pro (c.1073G>C) in the general population?

CDC73 p.Arg358Pro (c.1073G>C) is very rare (popmax 8.57e-05%, nfe) (gnomAD).

What do computational predictors say about CDC73 p.Arg358Pro (c.1073G>C)?

AlphaMissense predicts likely pathogenic (score 0.9917) — an in-silico prediction, not a clinical call.

CDC73 p.Arg358Pro

c.1073G>C · VCV3488500

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9917 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.57e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9917	likely pathogenic
REVEL	0.6	indeterminate
SaProt	LLR -13.40	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.40 · evaluated, not missing
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	29.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.57e-05% European (non-Finnish) · 1/1,166,556 alleles

Overall 6.28e-05% 1/1,593,192 alleles · very rare exomes 1/1,441,266 · genomes 0/151,926 · joint denominator

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.Arg358Pro
Coding: c.1073G>C
MANE Select: NM_024529
Type: single nucleotide variant
Location: chr1:193212396 (GRCh38)
Gene constraint: LOEUF 0.42 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.94 · 21 PDB
Residue 358: 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

Similar variants

CDC73 p.Arg358Gln Uncertain significance ★★ ⚠ same residue
CDC73 p.Arg358= Likely benign ★★ same residue
CDC73 p.Arg358Ter Pathogenic ★ 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 p.Arg120Ter Pathogenic ★★ same condition
CDC73 p.Arg126Ter Pathogenic/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-arg358pro (accessed [today's date]).

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