Is ITCH p.Gln433= (c.1299A>G) pathogenic?

ITCH p.Gln433= (c.1299A>G) is classified Likely benign in ITCH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-02). Very rare (popmax 0.00229%, nfe); Associated with syndromic multisystem autoimmune disease due to ITCH deficiency.

What condition is associated with ITCH p.Gln433= (c.1299A>G)?

ITCH p.Gln433= (c.1299A>G) is associated with syndromic multisystem autoimmune disease due to ITCH deficiency (ClinVar).

How common is ITCH p.Gln433= (c.1299A>G) in the general population?

ITCH p.Gln433= (c.1299A>G) is very rare (popmax 0.00229%, nfe) (gnomAD).

ITCH p.Gln433=

Q: How is Syndromic multisystem autoimmune disease due to Itch deficiency inherited?

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

c.1299A>G · rs1330053814 · VCV1581610

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00229%, nfe)

Conditions

syndromic multisystem autoimmune disease due to ITCH deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.37	acceptor gain · deltas
Constraint at this position
Conservation	phyloP -2.6	GERP -4.2
Overall
CADD	11.58	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00229% European (non-Finnish) · 27/1,179,818 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00167% 27/1,613,676 alleles · very rare exomes 25/1,461,444 · genomes 2/152,232 · joint denominator

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.Gln433=
Coding: c.1299A>G
MANE Select: NM_031483
dbSNP: rs1330053814
Type: single nucleotide variant
Location: chr20:34462096 (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 433: the 'required for interaction with fyn' region

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

Disease context

syndromic multisystem autoimmune disease due to ITCH deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Syndromic multisystem autoimmune disease due to Itch deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ITCH p.Gln433Arg Uncertain significance ★ ⚠ same residue
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.Arg763Ser Uncertain significance ★★ ⚠ same condition
ITCH p.Arg82Gly Uncertain significance ★★ ⚠ same condition
ITCH p.Arg82His 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-gln433 (accessed [today's date]).

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