Is JUP p.Pro735Ser (c.2203C>T) pathogenic?

JUP p.Pro735Ser (c.2203C>T) is classified Uncertain significance in JUP (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-03). AlphaMissense: likely benign (0.065); Very rare (popmax 0.000255%, nfe); Associated with Naxos disease.

What condition is associated with JUP p.Pro735Ser (c.2203C>T)?

JUP p.Pro735Ser (c.2203C>T) is associated with Naxos disease, arrhythmogenic right ventricular dysplasia 12 (ClinVar).

How common is JUP p.Pro735Ser (c.2203C>T) in the general population?

JUP p.Pro735Ser (c.2203C>T) is very rare (popmax 0.000255%, nfe) (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.Pro735Ser (c.2203C>T)?

AlphaMissense predicts likely benign (score 0.065) — an in-silico prediction, not a clinical call.

JUP p.Pro735Ser

c.2203C>T · rs1469855194 · VCV1915991

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.065 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000255%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Naxos disease

Computational evidence

Protein change
AlphaMissense	0.065	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	LLR -6.08	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.64	donor gain · deltas
Pangolin	Δ0.44	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.4	GERP 1.8, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 16 kb · p 5.2e-07 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000255% European (non-Finnish) · 3/1,178,562 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,611,284 alleles · very rare exomes 3/1,458,954 · genomes 0/152,330 · 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.Pro735Ser
Coding: c.2203C>T
MANE Select: NM_002230
dbSNP: rs1469855194
Type: single nucleotide variant
Location: chr17:41755779 (GRCh38)
Gene constraint: LOEUF 0.533 · pLI 0.74 (gnomAD)
Structure: AlphaFold pLDDT 80.88 · 1 PDB

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.Pro735Leu Uncertain significance ★★ ⚠ same residue
JUP p.Pro735Arg 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
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-pro735ser (accessed [today's date]).

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