Is JUP p.Ser595= (c.1785G>A) pathogenic?

JUP p.Ser595= (c.1785G>A) is classified Likely benign in JUP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-05). Very rare (popmax 0.00669%, amr); Associated with Cardiovascular phenotype.

What condition is associated with JUP p.Ser595= (c.1785G>A)?

JUP p.Ser595= (c.1785G>A) is associated with Cardiovascular phenotype, Naxos disease, arrhythmogenic right ventricular dysplasia 12 (ClinVar).

How common is JUP p.Ser595= (c.1785G>A) in the general population?

JUP p.Ser595= (c.1785G>A) is very rare (popmax 0.00669%, amr) (gnomAD).

JUP p.Ser595=

c.1785G>A · rs782816522 · VCV1561370

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00669%, amr)

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 -16	GERP -4.7
Overall
CADD	0.303	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00669% Admixed American · 4/59,766 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000745% 12/1,610,078 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00669%	14,941
East Asian	0.00223%	44,852
Remaining individualsnot grpmax-eligible	0.00161%	62,298
African / African-American	0.00134%	74,838
South Asian	0.00111%	90,400
European (non-Finnish)	0.00034%	294,512

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.Ser595=
Coding: c.1785G>A
MANE Select: NM_002230
dbSNP: rs782816522
Type: single nucleotide variant
Location: chr17:41757773 (GRCh38)
Gene constraint: LOEUF 0.533 · pLI 0.74 (gnomAD)
Structure: AlphaFold pLDDT 80.88 · 1 PDB
Residue 595: the 'interaction with dsc1' region

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 p.Ser595Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
JUP p.Ser595fs Pathogenic ★ 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.-1G>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-ser595 (accessed [today's date]).

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