Is CDC73 p.Leu95Pro (c.284T>C) pathogenic?

CDC73 p.Leu95Pro (c.284T>C) is classified Conflicting classifications of pathogenicity in CDC73 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-02-06). AlphaMissense: likely pathogenic (0.9992); Absent from gnomAD v4.1; Associated with Familial hyperparathyroidism or Hypocalciuric hypercalcaemia.

What condition is associated with CDC73 p.Leu95Pro (c.284T>C)?

CDC73 p.Leu95Pro (c.284T>C) is associated with Familial hyperparathyroidism or Hypocalciuric hypercalcaemia, parathyroid gland carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is CDC73 p.Leu95Pro (c.284T>C) in the general population?

CDC73 p.Leu95Pro (c.284T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDC73 p.Leu95Pro (c.284T>C)?

AlphaMissense predicts likely pathogenic (score 0.9992) — an in-silico prediction, not a clinical call.

CDC73 p.Leu95Pro

c.284T>C · rs2103117916 · VCV1501919

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9992 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,604,540)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Familial hyperparathyroidism or Hypocalciuric hypercalcaemia

Computational evidence

Protein change
AlphaMissense	0.9992	likely pathogenic · top 2% in CDC73
REVEL	0.948	strongly pathogenic-leaning
SaProt	LLR -14.61	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 16 kb · p 1.1e-08 · regional, not allelic
Overall
CADD	28.1	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

No allele count reported in gnomAD v4.1 (AN 1,604,540). 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.Leu95Pro
Coding: c.284T>C
MANE Select: NM_024529
dbSNP: rs2103117916
Type: single nucleotide variant
Location: chr1:193130220 (GRCh38)
Gene constraint: LOEUF 0.42 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.94 · 21 PDB
Residue 95: a UniProt-annotated variant site (in hrpt1; uncertain significance; found as somatic mutation in a parathyroid adenoma sample from a patient who also carries a germline frameshift mutation); an α-helix

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

Disease context

Familial hyperparathyroidism or Hypocalciuric hypercalcaemia

Also linked: parathyroid gland carcinoma hereditary neoplastic syndrome

Similar variants

CDC73 p.Leu95= Likely benign ★★ same residue
CDC73 p.Leu95Arg Likely pathogenic ★ same residue
CDC73 p.Leu95Phe Uncertain significance ★ ⚠ 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

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-leu95pro (accessed [today's date]).

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