Is JUP p.Phe581= (c.1743C>T) pathogenic?

JUP p.Phe581= (c.1743C>T) is classified Likely benign in JUP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-07). Very rare (popmax 6.84e-05%); Associated with Cardiovascular phenotype.

What condition is associated with JUP p.Phe581= (c.1743C>T)?

JUP p.Phe581= (c.1743C>T) is associated with Cardiovascular phenotype, Naxos disease, arrhythmogenic right ventricular dysplasia 12 (ClinVar).

How common is JUP p.Phe581= (c.1743C>T) in the general population?

JUP p.Phe581= (c.1743C>T) is very rare (popmax 6.84e-05%) (gnomAD).

JUP p.Phe581=

c.1743C>T · rs1005430954 · VCV2934921

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 0.068, phastCons 1
Overall
CADD	14.43	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.84e-05%

Overall 6.84e-05% 1/1,461,548 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: JUP
Protein: p.Phe581=
Coding: c.1743C>T
MANE Select: NM_002230
dbSNP: rs1005430954
Type: single nucleotide variant
Location: chr17:41758429 (GRCh38)
Gene constraint: LOEUF 0.533 · pLI 0.74 (gnomAD)
Structure: AlphaFold pLDDT 80.88 · 1 PDB
Residue 581: the 'interaction with dsc1' region; an α-helix

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

Disease context

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

Also linked: Naxos disease arrhythmogenic right ventricular dysplasia 12

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.-1G>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

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-phe581 (accessed [today's date]).

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