Is CDC73 p.Thr104Ser (c.310A>T) pathogenic?

CDC73 p.Thr104Ser (c.310A>T) is classified Uncertain significance in CDC73 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-23). AlphaMissense: likely benign (0.0741); Very rare (popmax 8.49e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CDC73 p.Thr104Ser (c.310A>T)?

CDC73 p.Thr104Ser (c.310A>T) is associated with hereditary neoplastic syndrome, hyperparathyroidism 1, hyperparathyroidism 2 with jaw tumors (ClinVar).

How common is CDC73 p.Thr104Ser (c.310A>T) in the general population?

CDC73 p.Thr104Ser (c.310A>T) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

What do computational predictors say about CDC73 p.Thr104Ser (c.310A>T)?

AlphaMissense predicts likely benign (score 0.0741) — an in-silico prediction, not a clinical call.

CDC73 p.Thr104Ser

c.310A>T · rs1675773683 · VCV952241

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0741 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0741	likely benign
REVEL	0.254	benign-leaning
SaProt	LLR -7.20	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>G here scores Δ0.95 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.3	GERP 0.62, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 16 kb · p 1.1e-08 · regional, not allelic
Overall
CADD	20.3	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

Grpmax group 8.49e-05% European (non-Finnish) · 1/1,178,506 alleles

Overall 6.85e-05% 1/1,460,088 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.Thr104Ser
Coding: c.310A>T
MANE Select: NM_024529
dbSNP: rs1675773683
Type: single nucleotide variant
Location: chr1:193135393 (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

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.Thr104= Likely benign ★★ same residue
CDC73 p.Thr104Ala Uncertain significance ★ ⚠ same residue
CDC73 p.Thr104Ile 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-thr104ser (accessed [today's date]).

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