Is JUP p.Arg320Ser (c.958C>A) pathogenic?

JUP p.Arg320Ser (c.958C>A) is classified Uncertain significance in JUP (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-03). AlphaMissense: ambiguous (0.5405); Absent from gnomAD v4.1; Associated with Naxos disease.

What condition is associated with JUP p.Arg320Ser (c.958C>A)?

JUP p.Arg320Ser (c.958C>A) is associated with Naxos disease, arrhythmogenic right ventricular dysplasia 12 (ClinVar).

How common is JUP p.Arg320Ser (c.958C>A) in the general population?

JUP p.Arg320Ser (c.958C>A) 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.Arg320Ser (c.958C>A)?

AlphaMissense predicts ambiguous (score 0.5405) — an in-silico prediction, not a clinical call.

JUP p.Arg320Ser

c.958C>A · rs200740462 · VCV1999759

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5405 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Naxos disease

Computational evidence

Protein change
AlphaMissense	0.5405	ambiguous
REVEL	0.445	indeterminate
SaProt	LLR -5.80	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.1	GERP 2.2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 16 kb · p 5.2e-07 · regional, not allelic
Overall
CADD	26.6	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

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.Arg320Ser
Coding: c.958C>A
MANE Select: NM_002230
dbSNP: rs200740462
Type: single nucleotide variant
Location: chr17:41765019 (GRCh38)
Gene constraint: LOEUF 0.533 · pLI 0.74 (gnomAD)
Structure: AlphaFold pLDDT 80.88 · 1 PDB
Residue 320: an α-helix

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 p.Arg320Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
JUP p.Arg320His Conflicting classifications of pathogenicity ★ ⚠ same residue
JUP p.Arg320Leu Uncertain significance ★ same residue
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

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-arg320ser (accessed [today's date]).

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