Is ITCH p.Leu69Phe (c.205C>T) pathogenic?

ITCH p.Leu69Phe (c.205C>T) is classified Uncertain significance in ITCH (ClinVar, Single submitter, 1 submitter; last evaluated 2019-11-15). AlphaMissense: likely benign (0.1435); Absent from gnomAD v4.1; Associated with syndromic multisystem autoimmune disease due to ITCH deficiency.

What condition is associated with ITCH p.Leu69Phe (c.205C>T)?

ITCH p.Leu69Phe (c.205C>T) is associated with syndromic multisystem autoimmune disease due to ITCH deficiency (ClinVar).

How common is ITCH p.Leu69Phe (c.205C>T) in the general population?

ITCH p.Leu69Phe (c.205C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ITCH p.Leu69Phe (c.205C>T)?

AlphaMissense predicts likely benign (score 0.1435) — an in-silico prediction, not a clinical call.

ITCH p.Leu69Phe

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.205C>T · rs1978516186 · VCV956075

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1435 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

syndromic multisystem autoimmune disease due to ITCH deficiency

Computational evidence

Protein change
AlphaMissense	0.1435	likely benign
REVEL	0.129	moderately benign-leaning
SaProt	LLR -8.04	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 32 kb · p 0.0051 · regional, not allelic
Overall
CADD	22.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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: ITCH
Protein: p.Leu69Phe
Coding: c.205C>T
MANE Select: NM_031483
dbSNP: rs1978516186
Type: single nucleotide variant
Location: chr20:34408785 (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 69: the c2 domain; a β-strand

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-leu69phe (accessed [today's date]).

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