Is JUP p.Ser665Pro (c.1993T>C) pathogenic?

JUP p.Ser665Pro (c.1993T>C) is classified Uncertain significance in JUP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2020-10-12). AlphaMissense: likely pathogenic (0.9995); Absent from gnomAD v4.1.

How common is JUP p.Ser665Pro (c.1993T>C) in the general population?

JUP p.Ser665Pro (c.1993T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about JUP p.Ser665Pro (c.1993T>C)?

AlphaMissense predicts likely pathogenic (score 0.9995) — an in-silico prediction, not a clinical call.

JUP p.Ser665Pro

c.1993T>C · rs1597780746 · VCV811420

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9995 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9995	likely pathogenic · top 5% in JUP
REVEL	0.722	pathogenic-leaning
SaProt	LLR -15.57	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 16 kb · p 5.2e-07 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: JUP
Protein: p.Ser665Pro
Coding: c.1993T>C
MANE Select: NM_002230
dbSNP: rs1597780746
Type: single nucleotide variant
Location: chr17:41757468 (GRCh38)
Gene constraint: LOEUF 0.533 · pLI 0.74 (gnomAD)
Structure: AlphaFold pLDDT 80.88 · 1 PDB
Residue 665: a modified residue (phosphoserine); an α-helix

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

Similar variants

JUP p.Ser665= Conflicting classifications of pathogenicity ★ same residue
JUP p.Ser665Phe Uncertain significance ★ ⚠ same residue
JUP c.1773+3G>A Uncertain significance ★★ same type
JUP c.468+4T>C Uncertain significance ★★ same type
JUP c.707+5C>A Uncertain significance ★★ same type
JUP c.-1G>A Uncertain significance ★★ same type
JUP c.*1026G>A Uncertain significance ★★ same type
JUP c.*1136C>T Uncertain significance ★★ same type

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-ser665pro (accessed [today's date]).

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