Is JUP p.Ser99= (c.297G>A) pathogenic?

JUP p.Ser99= (c.297G>A) is classified Conflicting classifications of pathogenicity in JUP (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-01-20). Rare (popmax 0.165%, mid); Associated with Cardiovascular phenotype.

What condition is associated with JUP p.Ser99= (c.297G>A)?

JUP p.Ser99= (c.297G>A) is associated with Cardiovascular phenotype, Naxos disease, arrhythmogenic right ventricular dysplasia 12 (ClinVar).

How common is JUP p.Ser99= (c.297G>A) in the general population?

JUP p.Ser99= (c.297G>A) is rare (popmax 0.165%, mid) (gnomAD).

JUP p.Ser99=

c.297G>A · rs200976464 · VCV45848

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

gnomAD v4.1

Rare

rare (popmax 0.165%, mid)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.24	acceptor gain · deltas
Pangolin	Δ0.26	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -13	GERP -4.7
Overall
CADD	2.155	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.165% Middle Eastern · 10/6,044 alleles

Filtering AF 0.0971% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0904%

Overall 0.0551% 885/1,605,758 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.212%	472
Middle Easterngrpmax	0.165%	604
Admixed American	0.118%	845
South Asian	0.115%	868
Remaining individualsnot grpmax-eligible	0.0547%	1,830
European (non-Finnish)	0.0509%	1,965
African / African-American	0.00667%	15,002
East Asian	0.00449%	22,272
Finnishnot grpmax-eligible	0.00159%	62,998

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser99=
Coding: c.297G>A
MANE Select: NM_002230
dbSNP: rs200976464
Type: single nucleotide variant
Location: chr17:41769589 (GRCh38)
Gene constraint: LOEUF 0.533 · pLI 0.74 (gnomAD)
Structure: AlphaFold pLDDT 80.88 · 1 PDB
Residue 99: a modified residue (phosphoserine)

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.Ser99Leu Conflicting classifications of pathogenicity ★ ⚠ 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-ser99 (accessed [today's date]).

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