Is JUP p.Ser77Phe (c.230C>T) pathogenic?

JUP p.Ser77Phe (c.230C>T) is classified Uncertain significance in JUP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-24). AlphaMissense: likely benign (0.2374); Very rare (popmax 0.00133%, afr); Associated with arrhythmogenic right ventricular dysplasia 12.

What condition is associated with JUP p.Ser77Phe (c.230C>T)?

JUP p.Ser77Phe (c.230C>T) is associated with arrhythmogenic right ventricular dysplasia 12, Naxos disease (ClinVar).

How common is JUP p.Ser77Phe (c.230C>T) in the general population?

JUP p.Ser77Phe (c.230C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about JUP p.Ser77Phe (c.230C>T)?

AlphaMissense predicts likely benign (score 0.2374) — an in-silico prediction, not a clinical call.

JUP p.Ser77Phe

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.230C>T · rs782771565 · VCV2443564

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2374 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

arrhythmogenic right ventricular dysplasia 12

Computational evidence

Protein change
AlphaMissense	0.2374	likely benign
REVEL	0.092	moderately benign-leaning
SaProt	LLR -8.85	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.1	GERP 1.3, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 16 kb · p 5.2e-07 · regional, not allelic
Overall
CADD	23.6	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 0.00133% African / African-American · 1/74,928 alleles

Overall 0.000186% 3/1,608,588 alleles · very rare exomes 2/1,456,368 · genomes 1/152,220 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,928
South Asian	0.00112%	89,598
European (non-Finnish)	8.49e-05%	1,178,391

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.Ser77Phe
Coding: c.230C>T
MANE Select: NM_002230
dbSNP: rs782771565
Type: single nucleotide variant
Location: chr17:41769656 (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

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.Ser77Pro 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
JUP c.*771G>C 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-ser77phe (accessed [today's date]).

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