Is JUP p.Pro692Ala (c.2074C>G) pathogenic?

JUP p.Pro692Ala (c.2074C>G) is classified Uncertain significance in JUP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-15). AlphaMissense: likely benign (0.0937); Absent from gnomAD v4.1; Associated with Naxos disease.

What condition is associated with JUP p.Pro692Ala (c.2074C>G)?

JUP p.Pro692Ala (c.2074C>G) is associated with Naxos disease, arrhythmogenic right ventricular dysplasia 12 (ClinVar).

How common is JUP p.Pro692Ala (c.2074C>G) in the general population?

JUP p.Pro692Ala (c.2074C>G) is absent from gnomAD v4.1 (gnomAD).

How is Naxos disease inherited?

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

What do computational predictors say about JUP p.Pro692Ala (c.2074C>G)?

AlphaMissense predicts likely benign (score 0.0937) — an in-silico prediction, not a clinical call.

JUP p.Pro692Ala

c.2074C>G · VCV3750670

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0937 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Naxos disease

Computational evidence

Protein change
AlphaMissense	0.0937	likely benign
REVEL	0.229	benign-leaning
SaProt	LLR -6.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.4, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 16 kb · p 5.2e-07 · regional, not allelic
Overall
CADD	19.69	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: JUP
Protein: p.Pro692Ala
Coding: c.2074C>G
MANE Select: NM_002230
Type: single nucleotide variant
Location: chr17:41756187 (GRCh38)
Gene constraint: LOEUF 0.533 · pLI 0.74 (gnomAD)
Structure: AlphaFold pLDDT 80.88 · 1 PDB

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

Disease context

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

Also linked: arrhythmogenic right ventricular dysplasia 12

For Naxos disease (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

JUP c.1773+3G>A Uncertain significance ★★ same condition
JUP c.468+4T>C Uncertain significance ★★ same condition
JUP c.707+5C>A Uncertain significance ★★ same condition
JUP c.*1026G>A Uncertain significance ★★ same condition
JUP c.*1136C>T Uncertain significance ★★ same condition
JUP c.*413C>T Uncertain significance ★★ same condition
JUP c.*771G>C Uncertain significance ★★ same condition
JUP c.*906A>C Uncertain significance ★★ 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/jup-p-pro692ala (accessed [today's date]).

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