Is CDC73 p.Pro349Leu (c.1046C>T) pathogenic?

CDC73 p.Pro349Leu (c.1046C>T) is classified Uncertain significance in CDC73 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-19). AlphaMissense: likely benign (0.1695); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with CDC73 p.Pro349Leu (c.1046C>T)?

CDC73 p.Pro349Leu (c.1046C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is CDC73 p.Pro349Leu (c.1046C>T) in the general population?

CDC73 p.Pro349Leu (c.1046C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDC73 p.Pro349Leu (c.1046C>T)?

AlphaMissense predicts likely benign (score 0.1695) — an in-silico prediction, not a clinical call.

CDC73 p.Pro349Leu

c.1046C>T · rs2102038080 · VCV1775499

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1695 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,585,236)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1695	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	LLR -8.16	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 109 kb · p 8.5e-19 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

No allele count reported in gnomAD v4.1 (AN 1,585,236). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CDC73
Protein: p.Pro349Leu
Coding: c.1046C>T
MANE Select: NM_024529
dbSNP: rs2102038080
Type: single nucleotide variant
Location: chr1:193212080 (GRCh38)
Gene constraint: LOEUF 0.42 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.94 · 21 PDB
Residue 349: 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.Pro349Thr Uncertain significance ★★ ⚠ same residue
CDC73 p.Pro349= 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 p.Arg120Ter Pathogenic ★★ same condition
CDC73 p.Arg126Ter Pathogenic/Likely pathogenic ★★ same condition
CDC73 p.Arg139Ter 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-pro349leu (accessed [today's date]).

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