Is ITCH p.Thr155= (c.465A>G) pathogenic?

ITCH p.Thr155= (c.465A>G) is classified Likely benign in ITCH (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-23). Rare (popmax 0.165%, mid); Associated with syndromic multisystem autoimmune disease due to ITCH deficiency.

What condition is associated with ITCH p.Thr155= (c.465A>G)?

ITCH p.Thr155= (c.465A>G) is associated with syndromic multisystem autoimmune disease due to ITCH deficiency (ClinVar).

How common is ITCH p.Thr155= (c.465A>G) in the general population?

ITCH p.Thr155= (c.465A>G) is rare (popmax 0.165%, mid) (gnomAD).

ITCH p.Thr155=

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.465A>G · rs868361524 · VCV1590955

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.165%, mid)

Conditions

syndromic multisystem autoimmune disease due to ITCH deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.35	GERP -3.2, phastCons 0.001
Overall
CADD	7.437	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.165% Middle Eastern · 10/6,054 alleles

Filtering AF 0.0896% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0681%

Overall 0.000868% 14/1,613,356 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.165%	605
Remaining individualsnot grpmax-eligible	0.0032%	31,236
South Asian	0.0011%	91,076
European (non-Finnish)	8.48e-05%	1,179,295

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.Thr155=
Coding: c.465A>G
MANE Select: NM_031483
dbSNP: rs868361524
Type: single nucleotide variant
Location: chr20:34413869 (GRCh38)
Gene constraint: LOEUF 0.343 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 76.39 · 12 PDB

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 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
ITCH p.Asn110Ser 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-thr155 (accessed [today's date]).

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