Is ITCH p.Arg763Ser (c.2289G>T) pathogenic?

ITCH p.Arg763Ser (c.2289G>T) is classified Uncertain significance in ITCH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-21). AlphaMissense: likely pathogenic (0.84); Very rare (popmax 0.00102%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ITCH p.Arg763Ser (c.2289G>T)?

ITCH p.Arg763Ser (c.2289G>T) is associated with Inborn genetic diseases, syndromic multisystem autoimmune disease due to ITCH deficiency (ClinVar).

How common is ITCH p.Arg763Ser (c.2289G>T) in the general population?

ITCH p.Arg763Ser (c.2289G>T) is very rare (popmax 0.00102%, nfe) (gnomAD).

What do computational predictors say about ITCH p.Arg763Ser (c.2289G>T)?

AlphaMissense predicts likely pathogenic (score 0.84) — an in-silico prediction, not a clinical call.

ITCH p.Arg763Ser

c.2289G>T · rs1234261647 · VCV575318

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.84 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.84	likely pathogenic
REVEL	0.145	moderately benign-leaning
SaProt	LLR -7.15	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -2.5, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 68 kb · p 1.5e-36 · regional, not allelic
Overall
CADD	20.9	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 R804S vs ClinVar R763S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00102% European (non-Finnish) · 12/1,179,858 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000821% 12/1,461,596 alleles · very rare

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.Arg763Ser
Coding: c.2289G>T
MANE Select: NM_031483
dbSNP: rs1234261647
Type: single nucleotide variant
Location: chr20:34489896 (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 763: 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

Also linked: syndromic multisystem autoimmune disease due to ITCH deficiency

Similar variants

ITCH c.1952+6T>C Uncertain significance ★★ same condition
ITCH p.Arg192Ser Uncertain significance ★★ ⚠ same condition
ITCH p.Arg217Gln Uncertain significance ★★ ⚠ same condition
ITCH p.Arg224Cys Uncertain significance ★★ ⚠ same condition
ITCH p.Arg82Gly Uncertain significance ★★ ⚠ same condition
ITCH p.Arg82His Uncertain significance ★★ ⚠ same condition
ITCH p.Asn110Ser Uncertain significance ★★ ⚠ same condition
ITCH p.Asn230Ser 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-arg763ser (accessed [today's date]).

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