Is CDC73 p.Pro138Thr (c.412C>A) pathogenic?

CDC73 p.Pro138Thr (c.412C>A) is classified Conflicting classifications of pathogenicity in CDC73 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-17). AlphaMissense: likely benign (0.2751); Very rare (popmax 0.0067%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with CDC73 p.Pro138Thr (c.412C>A)?

CDC73 p.Pro138Thr (c.412C>A) is associated with hereditary neoplastic syndrome, endocrine gland neoplasm, hyperparathyroidism 1 (ClinVar).

How common is CDC73 p.Pro138Thr (c.412C>A) in the general population?

CDC73 p.Pro138Thr (c.412C>A) is very rare (popmax 0.0067%, eas) (gnomAD).

What do computational predictors say about CDC73 p.Pro138Thr (c.412C>A)?

AlphaMissense predicts likely benign (score 0.2751) — an in-silico prediction, not a clinical call.

CDC73 p.Pro138Thr

c.412C>A · rs369542555 · VCV133842

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.2751 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0067%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2751	likely benign
REVEL	0.493	indeterminate
SaProt	LLR -8.94	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.1, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 16 kb · p 1.1e-08 · regional, not allelic
Overall
CADD	24.3	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 0.0067% East Asian · 3/44,798 alleles

Filtering AF 0.00178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000892%

Overall 0.00048% 7/1,458,686 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0067%	14,933
South Asian	0.0033%	30,322
Remaining individualsnot grpmax-eligible	0.0016%	62,374

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.Pro138Thr
Coding: c.412C>A
MANE Select: NM_024529
dbSNP: rs369542555
Type: single nucleotide variant
Location: chr1:193135578 (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: endocrine gland neoplasm hyperparathyroidism 1 parathyroid gland carcinoma

Similar variants

CDC73 p.Pro138Ala Uncertain significance ★★ ⚠ same residue
CDC73 p.Pro138Arg Uncertain significance ★ same residue
CDC73 p.Pro138Leu Uncertain significance ★ ⚠ same residue
CDC73 p.Pro138= 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

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-pro138thr (accessed [today's date]).

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