Is ITCH p.Met445Val (c.1333A>G) pathogenic?

ITCH p.Met445Val (c.1333A>G) is classified Conflicting classifications of pathogenicity in ITCH (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-06). AlphaMissense: ambiguous (0.5087); Very rare (popmax 0.00223%, eas); Associated with syndromic multisystem autoimmune disease due to ITCH deficiency.

What condition is associated with ITCH p.Met445Val (c.1333A>G)?

ITCH p.Met445Val (c.1333A>G) is associated with syndromic multisystem autoimmune disease due to ITCH deficiency (ClinVar).

How common is ITCH p.Met445Val (c.1333A>G) in the general population?

ITCH p.Met445Val (c.1333A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ITCH p.Met445Val (c.1333A>G)?

AlphaMissense predicts ambiguous (score 0.5087) — an in-silico prediction, not a clinical call.

ITCH p.Met445Val

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.1333A>G · rs150653226 · VCV1131454

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5087 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

syndromic multisystem autoimmune disease due to ITCH deficiency

Computational evidence

Protein change
AlphaMissense	0.5087	ambiguous
REVEL	0.495	indeterminate
SaProt	LLR -8.41	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 68 kb · p 1.5e-36 · regional, not allelic
Overall
CADD	26.1	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 M486V vs ClinVar M445V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,858 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.0122% 197/1,613,708 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.51%	196
Remaining individualsnot grpmax-eligible	0.0352%	2,840
East Asiangrpmax	0.00223%	44,858
European (non-Finnish)	0.00195%	51,294

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Met445Val
Coding: c.1333A>G
MANE Select: NM_031483
dbSNP: rs150653226
Type: single nucleotide variant
Location: chr20:34462130 (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 486 UniProt numbering: the ww 4 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 p.Met445Ile 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-met445val (accessed [today's date]).

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