Is ITK p.Arg394Trp (c.1180C>T) pathogenic?

ITK p.Arg394Trp (c.1180C>T) is classified Uncertain significance in ITK (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-25). AlphaMissense: likely benign (0.2458); Very rare (popmax 0.00267%, afr).

How common is ITK p.Arg394Trp (c.1180C>T) in the general population?

ITK p.Arg394Trp (c.1180C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about ITK p.Arg394Trp (c.1180C>T)?

AlphaMissense predicts likely benign (score 0.2458) — an in-silico prediction, not a clinical call.

ITK p.Arg394Trp

c.1180C>T · VCV4082453

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2458 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2458	likely benign
REVEL	0.48	indeterminate
SaProt	LLR -15.26	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP -0.14, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 63 kb · p 2.1e-06 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,822 alleles

Filtering AF 0.000444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000744% 12/1,613,844 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,411
Remaining individualsnot grpmax-eligible	0.0016%	62,482
European (non-Finnish)	0.000763%	131,112

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: ITK
Protein: p.Arg394Trp
Coding: c.1180C>T
MANE Select: NM_005546
Type: single nucleotide variant
Location: chr5:157243742 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.82 · 37 PDB
Residue 394: the protein kinase domain

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

Similar variants

ITK p.Arg394Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
ITK p.Arg562Ter Pathogenic/Likely pathogenic ★★ same type
ITK c.851+5G>A Uncertain significance ★★ same type
ITK p.Ala191Thr Uncertain significance ★★ ⚠ same type
ITK p.Ala261Thr Uncertain significance ★★ ⚠ same type
ITK p.Ala308Ser Uncertain significance ★★ ⚠ same type
ITK p.Ala345Val Uncertain significance ★★ ⚠ same type
ITK p.Ala471Thr Uncertain significance ★★ ⚠ same type

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/itk-p-arg394trp (accessed [today's date]).

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