Is ITCH p.Arg598Cys (c.1792C>T) pathogenic?

ITCH p.Arg598Cys (c.1792C>T) is classified Uncertain significance in ITCH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-19). AlphaMissense: likely benign (0.3129); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with ITCH p.Arg598Cys (c.1792C>T)?

ITCH p.Arg598Cys (c.1792C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ITCH p.Arg598Cys (c.1792C>T) in the general population?

ITCH p.Arg598Cys (c.1792C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ITCH p.Arg598Cys (c.1792C>T)?

AlphaMissense predicts likely benign (score 0.3129) — an in-silico prediction, not a clinical call.

ITCH p.Arg598Cys

c.1792C>T · VCV3530265

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3129 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3129	likely benign
REVEL	0.226	benign-leaning
SaProt	LLR -11.14	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 1.3, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 68 kb · p 1.5e-36 · regional, not allelic
Overall
CADD	28.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R639C vs ClinVar R598C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,854 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00041% 6/1,461,682 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,854
Finnishnot grpmax-eligible	0.00156%	63,904
European (non-Finnish)	0.000339%	294,993

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: ITCH
Protein: p.Arg598Cys
Coding: c.1792C>T
MANE Select: NM_031483
Type: single nucleotide variant
Location: chr20:34479763 (GRCh38)
Gene constraint: LOEUF 0.343 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 76.39 · 12 PDB
Residue 598: the hect domain; an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ITCH p.Arg217Gln Uncertain significance ★★ ⚠ same condition
ITCH p.Arg763Ser Uncertain significance ★★ ⚠ same condition
ITCH p.Arg82Gly Uncertain significance ★★ ⚠ same condition
ITCH p.Asn110Ser Uncertain significance ★★ ⚠ same condition
ITCH p.Asn410Ser Uncertain significance ★★ ⚠ same condition
ITCH p.Asn417Ser Uncertain significance ★★ ⚠ same condition
ITCH p.Asp140Asn Uncertain significance ★★ ⚠ same condition
ITCH p.Glu694Asp 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/itch-p-arg598cys (accessed [today's date]).

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