Is ITK p.Thr348Ile (c.1043C>T) pathogenic?

ITK p.Thr348Ile (c.1043C>T) is classified Uncertain significance in ITK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-12-07). AlphaMissense: ambiguous (0.5596); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with ITK p.Thr348Ile (c.1043C>T)?

ITK p.Thr348Ile (c.1043C>T) is associated with Inborn genetic diseases, lymphoproliferative syndrome 1 (ClinVar).

How common is ITK p.Thr348Ile (c.1043C>T) in the general population?

ITK p.Thr348Ile (c.1043C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ITK p.Thr348Ile (c.1043C>T)?

AlphaMissense predicts ambiguous (score 0.5596) — an in-silico prediction, not a clinical call.

ITK p.Thr348Ile

c.1043C>T · rs1358243764 · VCV2278452

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5596 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5596	ambiguous
REVEL	0.366	indeterminate
SaProt	LLR -8.62	tolerated
Splicing
SpliceAI	Δ0.23	donor loss · deltas
Pangolin	Δ0.24	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 6.1	GERP 0.89, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 63 kb · p 2.1e-06 · regional, not allelic
Overall
CADD	18.42	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

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: ITK
Protein: p.Thr348Ile
Coding: c.1043C>T
MANE Select: NM_005546
dbSNP: rs1358243764
Type: single nucleotide variant
Location: chr5:157241703 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.82 · 37 PDB

Full ITK 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: lymphoproliferative syndrome 1

Similar variants

ITK p.Thr348Arg Uncertain significance ★★ ⚠ same residue
ITK p.Thr348= Likely benign ★ same residue
ITK c.851+5G>A Uncertain significance ★★ same condition
ITK p.Ala191Thr Uncertain significance ★★ ⚠ same condition
ITK p.Ala261Thr Uncertain significance ★★ ⚠ same condition
ITK p.Ala308Ser Uncertain significance ★★ ⚠ same condition
ITK p.Ala345Val Uncertain significance ★★ ⚠ same condition
ITK p.Ala471Thr 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/itk-p-thr348ile (accessed [today's date]).

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