Is CDC73 p.Ala154Val (c.461C>T) pathogenic?

CDC73 p.Ala154Val (c.461C>T) is classified Uncertain significance in CDC73 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-02). AlphaMissense: ambiguous (0.5341); Very rare (popmax 0.000657%); Associated with parathyroid gland carcinoma.

What condition is associated with CDC73 p.Ala154Val (c.461C>T)?

CDC73 p.Ala154Val (c.461C>T) is associated with parathyroid gland carcinoma (ClinVar).

How common is CDC73 p.Ala154Val (c.461C>T) in the general population?

CDC73 p.Ala154Val (c.461C>T) is very rare (popmax 0.000657%) (gnomAD).

How is Parathyroid carcinoma inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CDC73 p.Ala154Val (c.461C>T)?

AlphaMissense predicts ambiguous (score 0.5341) — an in-silico prediction, not a clinical call.

CDC73 p.Ala154Val

c.461C>T · VCV3664232

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5341 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000657%)

Conditions

parathyroid gland carcinoma

Computational evidence

Protein change
AlphaMissense	0.5341	ambiguous
REVEL	0.41	indeterminate
SaProt	LLR -9.38	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.07	constrained · MANE · 3,817 bp · p 1.2e-12 · regional, not allelic
Overall
CADD	24.9	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

Grpmax group 0.000657%

Overall 0.000657% 1/152,114 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.Ala154Val
Coding: c.461C>T
MANE Select: NM_024529
Type: single nucleotide variant
Location: chr1:193138122 (GRCh38)
Gene constraint: LOEUF 0.42 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.94 · 21 PDB

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

Disease context

parathyroid gland carcinoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Parathyroid carcinoma (Orphanet):

Inheritance: Not applicable
Onset: Adult
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

CDC73 p.Ala154= 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-ala154val (accessed [today's date]).

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