Is CDC73 p.Ala377Thr (c.1129G>A) pathogenic?

CDC73 p.Ala377Thr (c.1129G>A) is classified Uncertain significance in CDC73 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-08-04). AlphaMissense: ambiguous (0.3596); Absent from gnomAD v4.1; Associated with hyperparathyroidism 1.

What condition is associated with CDC73 p.Ala377Thr (c.1129G>A)?

CDC73 p.Ala377Thr (c.1129G>A) is associated with hyperparathyroidism 1, hyperparathyroidism 2 with jaw tumors, parathyroid gland carcinoma (ClinVar).

How common is CDC73 p.Ala377Thr (c.1129G>A) in the general population?

CDC73 p.Ala377Thr (c.1129G>A) is absent from gnomAD v4.1 (gnomAD).

How is Familial isolated hyperparathyroidism inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CDC73 p.Ala377Thr (c.1129G>A)?

AlphaMissense predicts ambiguous (score 0.3596) — an in-silico prediction, not a clinical call.

CDC73 p.Ala377Thr

c.1129G>A · rs1677295843 · VCV935909

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3596 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,603,298)

Conditions

hyperparathyroidism 1

Computational evidence

Protein change
AlphaMissense	0.3596	ambiguous
REVEL	0.465	indeterminate
SaProt	LLR -9.76	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 2, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 109 kb · p 8.5e-19 · regional, not allelic
Overall
CADD	28.4	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 1,603,298). 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.Ala377Thr
Coding: c.1129G>A
MANE Select: NM_024529
dbSNP: rs1677295843
Type: single nucleotide variant
Location: chr1:193212452 (GRCh38)
Gene constraint: LOEUF 0.42 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.94 · 21 PDB
Residue 377: 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

hyperparathyroidism 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hyperparathyroidism 2 with jaw tumors parathyroid gland carcinoma hereditary neoplastic syndrome

For Familial isolated hyperparathyroidism (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

CDC73 p.Ala377Gly Uncertain significance ★★ ⚠ same residue
CDC73 p.Ala377Val Uncertain significance ★★ ⚠ same residue
CDC73 p.Ala377= Likely benign ★★ same residue
CDC73 p.Ala377Pro 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

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-ala377thr (accessed [today's date]).

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