Is ITK p.Thr348Arg (c.1043C>G) pathogenic?

ITK p.Thr348Arg (c.1043C>G) is classified Uncertain significance in ITK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-12). AlphaMissense: ambiguous (0.4969); Very rare (popmax 0.00017%, nfe); Associated with lymphoproliferative syndrome 1.

What condition is associated with ITK p.Thr348Arg (c.1043C>G)?

ITK p.Thr348Arg (c.1043C>G) is associated with lymphoproliferative syndrome 1 (ClinVar).

How common is ITK p.Thr348Arg (c.1043C>G) in the general population?

ITK p.Thr348Arg (c.1043C>G) is very rare (popmax 0.00017%, nfe) (gnomAD).

How is Combined immunodeficiency due to ITK deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ITK p.Thr348Arg (c.1043C>G)?

AlphaMissense predicts ambiguous (score 0.4969) — an in-silico prediction, not a clinical call.

ITK p.Thr348Arg

c.1043C>G · rs1358243764 · VCV1423059

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4969 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

lymphoproliferative syndrome 1

Computational evidence

Protein change
AlphaMissense	0.4969	ambiguous
REVEL	0.476	indeterminate
SaProt	LLR -6.99	tolerated
Splicing
SpliceAI	Δ0.32	donor loss · deltas
Pangolin	Δ0.32	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	20.6	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 0.00017% European (non-Finnish) · 2/1,179,362 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.00131% 2/152,180 alleles · very rare

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.Thr348Arg
Coding: c.1043C>G
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

lymphoproliferative syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Combined immunodeficiency due to ITK deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood

Similar variants

ITK p.Thr348Ile 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-thr348arg (accessed [today's date]).

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