Is JAG1 p.Ser577Arg (c.1731C>G) pathogenic?

JAG1 p.Ser577Arg (c.1731C>G) is classified Pathogenic in JAG1 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-02-26). AlphaMissense: likely pathogenic (0.9812); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease, axonal, Type 2HH.

What condition is associated with JAG1 p.Ser577Arg (c.1731C>G)?

JAG1 p.Ser577Arg (c.1731C>G) is associated with Charcot-Marie-Tooth disease, axonal, Type 2HH (ClinVar).

How common is JAG1 p.Ser577Arg (c.1731C>G) in the general population?

JAG1 p.Ser577Arg (c.1731C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about JAG1 p.Ser577Arg (c.1731C>G)?

AlphaMissense predicts likely pathogenic (score 0.9812) — an in-silico prediction, not a clinical call.

JAG1 p.Ser577Arg

c.1731C>G · rs2122606362 · VCV1300241

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9812 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease, axonal, Type 2HH

Computational evidence

Protein change
AlphaMissense	0.9812	likely pathogenic ✓ concordant with ClinVar
REVEL	0.662	pathogenic-leaning
SaProt	LLR -7.95	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP -0.059, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 5,169 bp · p 3.3e-11 · regional, not allelic
Overall
CADD	26.6	PHRED · no single calibrated threshold — expert panels disagree

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: JAG1
Protein: p.Ser577Arg
Coding: c.1731C>G
MANE Select: NM_000214
dbSNP: rs2122606362
Type: single nucleotide variant
Location: chr20:10647093 (GRCh38)
Gene constraint: LOEUF 0.211 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.02 · 7 PDB
Residue 577: a UniProt-annotated variant site (in cmt2hh; decreased glycosylation; decreased expression at the cell membrane due to partial retention in the endoplasmic reticulum)

Full JAG1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease, axonal, Type 2HH — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

JAG1 c.2113+1G>A Likely pathogenic ★★ same condition
JAG1 c.439+1G>A Pathogenic ★★ same condition
JAG1 p.Arg184Cys Pathogenic/Likely pathogenic ★★ same condition
JAG1 p.Arg184His Pathogenic/Likely pathogenic ★★ same condition
JAG1 p.Arg235Ter Pathogenic ★★ same condition
JAG1 p.Arg744Ter Pathogenic ★★ same condition
JAG1 c.3048+7A>G Uncertain significance ★★ same condition
JAG1 c.-75A>G 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/jag1-p-ser577arg (accessed [today's date]).

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