Is ITCH p.Val73Ile (c.217G>A) pathogenic?

ITCH p.Val73Ile (c.217G>A) is classified Uncertain significance in ITCH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-09-13). AlphaMissense: likely benign (0.1812); Very rare (popmax 0.00331%, sas); Associated with syndromic multisystem autoimmune disease due to ITCH deficiency.

What condition is associated with ITCH p.Val73Ile (c.217G>A)?

ITCH p.Val73Ile (c.217G>A) is associated with syndromic multisystem autoimmune disease due to ITCH deficiency (ClinVar).

How common is ITCH p.Val73Ile (c.217G>A) in the general population?

ITCH p.Val73Ile (c.217G>A) is very rare (popmax 0.00331%, sas) (gnomAD).

What do computational predictors say about ITCH p.Val73Ile (c.217G>A)?

AlphaMissense predicts likely benign (score 0.1812) — an in-silico prediction, not a clinical call.

ITCH p.Val73Ile

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.217G>A · rs776445457 · VCV947149

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1812 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00331%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

syndromic multisystem autoimmune disease due to ITCH deficiency

Computational evidence

Protein change
AlphaMissense	0.1812	likely benign
REVEL	0.326	indeterminate
SaProt	LLR -9.51	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 32 kb · p 0.0051 · regional, not allelic
Overall
CADD	26.0	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

Grpmax group 0.00331% South Asian · 3/90,640 alleles

Filtering AF 0.000879% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000444%

Overall 0.000879% 14/1,591,940 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00331%	30,213
East Asian	0.00224%	44,656
European (non-Finnish)	0.000862%	116,040

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.Val73Ile
Coding: c.217G>A
MANE Select: NM_031483
dbSNP: rs776445457
Type: single nucleotide variant
Location: chr20:34412519 (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 73: 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-val73ile (accessed [today's date]).

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