Is JUP p.Ser653= (c.1959C>T) pathogenic?

JUP p.Ser653= (c.1959C>T) is classified Conflicting classifications of pathogenicity in JUP (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-04-02). Ultra-rare (popmax 0.0116%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with JUP p.Ser653= (c.1959C>T)?

JUP p.Ser653= (c.1959C>T) is associated with Cardiovascular phenotype, cardiomyopathy, Naxos disease (ClinVar).

How common is JUP p.Ser653= (c.1959C>T) in the general population?

JUP p.Ser653= (c.1959C>T) is ultra-rare (popmax 0.0116%, nfe) (gnomAD).

JUP p.Ser653=

c.1959C>T · rs375451560 · VCV178040

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0116%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -6.4	GERP -4.4
Overall
CADD	1.521	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0116% European (non-Finnish) · 137/1,180,044 alleles

Filtering AF 0.01% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00939%

Overall 0.00905% 146/1,614,078 alleles · ultra-rare exomes 129/1,461,882 · genomes 17/152,196 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0116%	8,613
African / African-American	0.00801%	12,487
Admixed American	0.00167%	60,002
Remaining individualsnot grpmax-eligible	0.0016%	62,486
South Asian	0.0011%	91,092

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.Ser653=
Coding: c.1959C>T
MANE Select: NM_002230
dbSNP: rs375451560
Type: single nucleotide variant
Location: chr17:41757502 (GRCh38)
Gene constraint: LOEUF 0.533 · pLI 0.74 (gnomAD)
Structure: AlphaFold pLDDT 80.88 · 1 PDB
Residue 653: 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: cardiomyopathy Naxos disease arrhythmogenic right ventricular dysplasia 12

Similar variants

JUP p.Ser653Phe 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.-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

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-ser653 (accessed [today's date]).

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