Is ITCH p.Ser239Ile (c.716G>T) pathogenic?

ITCH p.Ser239Ile (c.716G>T) is classified Uncertain significance in ITCH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-09). AlphaMissense: likely benign (0.1028); Ultra-rare (popmax 0.0446%, eas); Associated with Inborn genetic diseases.

What condition is associated with ITCH p.Ser239Ile (c.716G>T)?

ITCH p.Ser239Ile (c.716G>T) is associated with Inborn genetic diseases, syndromic multisystem autoimmune disease due to ITCH deficiency (ClinVar).

How common is ITCH p.Ser239Ile (c.716G>T) in the general population?

ITCH p.Ser239Ile (c.716G>T) is ultra-rare (popmax 0.0446%, eas) (gnomAD).

What do computational predictors say about ITCH p.Ser239Ile (c.716G>T)?

AlphaMissense predicts likely benign (score 0.1028) — an in-silico prediction, not a clinical call.

ITCH p.Ser239Ile

c.716G>T · rs145113977 · VCV2060422

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1028 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1028	likely benign
REVEL	0.068	moderately benign-leaning
SaProt	LLR -7.66	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 9.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 32 kb · p 0.0051 · regional, not allelic
Overall
CADD	22.1	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S280I vs ClinVar S239I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0446% East Asian · 20/44,890 alleles

Filtering AF 0.0295% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0246%

Overall 0.00143% 23/1,613,704 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0446%	2,244
African / African-American	0.00267%	37,451
European (non-Finnish)	8.48e-05%	1,179,746

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.Ser239Ile
Coding: c.716G>T
MANE Select: NM_031483
dbSNP: rs145113977
Type: single nucleotide variant
Location: chr20:34440191 (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 239: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: syndromic multisystem autoimmune disease due to ITCH deficiency

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-ser239ile (accessed [today's date]).

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