Is CDC73 p.Phe511Leu (c.1533C>A) pathogenic?

CDC73 p.Phe511Leu (c.1533C>A) is classified Uncertain significance in CDC73 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-08). AlphaMissense: likely pathogenic (0.7572); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with CDC73 p.Phe511Leu (c.1533C>A)?

CDC73 p.Phe511Leu (c.1533C>A) is associated with hereditary neoplastic syndrome, hyperparathyroidism 1, hyperparathyroidism 2 with jaw tumors (ClinVar).

How common is CDC73 p.Phe511Leu (c.1533C>A) in the general population?

CDC73 p.Phe511Leu (c.1533C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDC73 p.Phe511Leu (c.1533C>A)?

AlphaMissense predicts likely pathogenic (score 0.7572) — an in-silico prediction, not a clinical call.

CDC73 p.Phe511Leu

c.1533C>A · rs2102073575 · VCV3227862

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7572 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.7572	likely pathogenic
REVEL	0.204	benign-leaning
SaProt	LLR -1.09	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 109 kb · p 8.5e-19 · regional, not allelic
Overall
CADD	17.36	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CDC73
Protein: p.Phe511Leu
Coding: c.1533C>A
MANE Select: NM_024529
dbSNP: rs2102073575
Type: single nucleotide variant
Location: chr1:193249845 (GRCh38)
Gene constraint: LOEUF 0.42 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.94 · 21 PDB
Residue 511: the 'interaction with polr2a and paf1' region; 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 hyperparathyroidism 2 with jaw tumors parathyroid gland carcinoma

Similar variants

CDC73 p.Phe511= 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
CDC73 c.513-1G>A Likely 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-phe511leu (accessed [today's date]).

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