Is JUP p.Pro677= (c.2031G>A) pathogenic?

JUP p.Pro677= (c.2031G>A) is classified Conflicting classifications of pathogenicity in JUP (ClinVar, Conflicting submitters, 14 submitters; last evaluated 2026-02-03). Ultra-rare (popmax 0.099%, mid); Associated with Cardiovascular phenotype.

What condition is associated with JUP p.Pro677= (c.2031G>A)?

JUP p.Pro677= (c.2031G>A) is associated with Cardiovascular phenotype, cardiomyopathy, Naxos disease (ClinVar).

How common is JUP p.Pro677= (c.2031G>A) in the general population?

JUP p.Pro677= (c.2031G>A) is ultra-rare (popmax 0.099%, mid) (gnomAD).

JUP p.Pro677=

c.2031G>A · rs188888662 · VCV137961

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 14 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.099%, mid)

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 -9.2	GERP -4.7
Overall
CADD	0.53	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.099% Middle Eastern · 6/6,062 alleles

Filtering AF 0.043% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0294%

Overall 0.0209% 338/1,614,220 alleles · ultra-rare exomes 307/1,461,884 · genomes 31/152,336 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.099%	1,010
Remaining individualsnot grpmax-eligible	0.0272%	3,677
European (non-Finnish)	0.0247%	4,041
African / African-American	0.0147%	6,824
Admixed American	0.00833%	12,004
South Asian	0.00659%	15,180
Finnishnot grpmax-eligible	0.00156%	64,028

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.Pro677=
Coding: c.2031G>A
MANE Select: NM_002230
dbSNP: rs188888662
Type: single nucleotide variant
Location: chr17:41757430 (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

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.Pro677Gln Uncertain significance ★ ⚠ same residue
JUP p.Pro677Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
JUP p.Pro677Ser 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

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-pro677 (accessed [today's date]).

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