Is CDC73 p.Val131Ile (c.391G>A) pathogenic?

CDC73 p.Val131Ile (c.391G>A) is classified Conflicting classifications of pathogenicity in CDC73 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-03). AlphaMissense: likely benign (0.0676); Very rare (popmax 0.00833%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with CDC73 p.Val131Ile (c.391G>A)?

CDC73 p.Val131Ile (c.391G>A) is associated with hereditary neoplastic syndrome, hyperparathyroidism 1, parathyroid gland carcinoma (ClinVar).

How common is CDC73 p.Val131Ile (c.391G>A) in the general population?

CDC73 p.Val131Ile (c.391G>A) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about CDC73 p.Val131Ile (c.391G>A)?

AlphaMissense predicts likely benign (score 0.0676) — an in-silico prediction, not a clinical call.

CDC73 p.Val131Ile

c.391G>A · rs769052041 · VCV462761

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0676 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0676	likely benign
REVEL	0.323	indeterminate
SaProt	LLR -7.33	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 9.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 16 kb · p 1.1e-08 · regional, not allelic
Overall
CADD	22.6	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 0.00833% Admixed American · 5/59,990 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000496% 8/1,613,452 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	11,998
European (non-Finnish)	0.000254%	393,221

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.Val131Ile
Coding: c.391G>A
MANE Select: NM_024529
dbSNP: rs769052041
Type: single nucleotide variant
Location: chr1:193135557 (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 parathyroid gland carcinoma

Similar variants

CDC73 p.Val131= Likely benign ★★ same residue
CDC73 p.Val131Asp Uncertain significance ★ ⚠ same residue
CDC73 p.Val131Leu Uncertain significance ★ ⚠ same residue
CDC73 p.Val131Phe 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-val131ile (accessed [today's date]).

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