Is JUP p.Ser175Pro (c.523T>C) pathogenic?

JUP p.Ser175Pro (c.523T>C) is classified Uncertain significance in JUP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-25). AlphaMissense: likely pathogenic (0.8077); Very rare (popmax 8.47e-05%, nfe); Associated with arrhythmogenic right ventricular dysplasia 12.

What condition is associated with JUP p.Ser175Pro (c.523T>C)?

JUP p.Ser175Pro (c.523T>C) is associated with arrhythmogenic right ventricular dysplasia 12, Naxos disease (ClinVar).

How common is JUP p.Ser175Pro (c.523T>C) in the general population?

JUP p.Ser175Pro (c.523T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about JUP p.Ser175Pro (c.523T>C)?

AlphaMissense predicts likely pathogenic (score 0.8077) — an in-silico prediction, not a clinical call.

JUP p.Ser175Pro

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.523T>C · VCV3759883

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8077 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

arrhythmogenic right ventricular dysplasia 12

Computational evidence

Protein change
AlphaMissense	0.8077	likely pathogenic
REVEL	0.411	indeterminate
SaProt	LLR -8.85	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 16 kb · p 5.2e-07 · regional, not allelic
Overall
CADD	26.0	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,952 alleles

Overall 6.22e-05% 1/1,606,528 alleles · very rare exomes 1/1,454,308 · genomes 0/152,220 · joint denominator

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.Ser175Pro
Coding: c.523T>C
MANE Select: NM_002230
Type: single nucleotide variant
Location: chr17:41769153 (GRCh38)
Gene constraint: LOEUF 0.533 · pLI 0.74 (gnomAD)
Structure: AlphaFold pLDDT 80.88 · 1 PDB
Residue 175: the 'interaction with dsc1 and dsg1' region; an α-helix

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

Disease context

arrhythmogenic right ventricular dysplasia 12 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Naxos disease

For Inherited isolated arrhythmogenic cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: No data available

Similar variants

JUP p.Ser175Leu Uncertain significance ★★ ⚠ same residue
JUP p.Ser175= Benign/Likely benign ★★ 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
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-ser175pro (accessed [today's date]).

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