Is ITCH p.Pro438Arg (c.1313C>G) pathogenic?

ITCH p.Pro438Arg (c.1313C>G) is classified Uncertain significance in ITCH (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-05). AlphaMissense: ambiguous (0.5512); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with ITCH p.Pro438Arg (c.1313C>G)?

ITCH p.Pro438Arg (c.1313C>G) is associated with Inborn genetic diseases (ClinVar).

How common is ITCH p.Pro438Arg (c.1313C>G) in the general population?

ITCH p.Pro438Arg (c.1313C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ITCH p.Pro438Arg (c.1313C>G)?

AlphaMissense predicts ambiguous (score 0.5512) — an in-silico prediction, not a clinical call.

ITCH p.Pro438Arg

c.1313C>G · rs2515774444 · VCV2305423

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5512 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5512	ambiguous
REVEL	0.579	indeterminate
SaProt	LLR -12.61	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 68 kb · p 1.5e-36 · regional, not allelic
Overall
CADD	31.0	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 P479R vs ClinVar P438R) — verify the residue.

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.Pro438Arg
Coding: c.1313C>G
MANE Select: NM_031483
dbSNP: rs2515774444
Type: single nucleotide variant
Location: chr20:34462110 (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 438: the ww 3 domain; the 'required for interaction with fyn' 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

Similar variants

ITCH p.Arg217Gln Uncertain significance ★★ ⚠ same condition
ITCH p.Arg763Ser Uncertain significance ★★ ⚠ same condition
ITCH p.Arg82Gly Uncertain significance ★★ ⚠ same condition
ITCH p.Asn110Ser Uncertain significance ★★ ⚠ same condition
ITCH p.Asn410Ser Uncertain significance ★★ ⚠ same condition
ITCH p.Asn417Ser Uncertain significance ★★ ⚠ same condition
ITCH p.Asp140Asn Uncertain significance ★★ ⚠ same condition
ITCH p.Glu694Asp 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-pro438arg (accessed [today's date]).

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