Is ITK p.Phe124Leu (c.370T>C) pathogenic?

ITK p.Phe124Leu (c.370T>C) is classified Uncertain significance in ITK (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-11). AlphaMissense: likely pathogenic (0.9174); Absent from gnomAD v4.1; Associated with lymphoproliferative syndrome 1.

What condition is associated with ITK p.Phe124Leu (c.370T>C)?

ITK p.Phe124Leu (c.370T>C) is associated with lymphoproliferative syndrome 1 (ClinVar).

How common is ITK p.Phe124Leu (c.370T>C) in the general population?

ITK p.Phe124Leu (c.370T>C) is absent from gnomAD v4.1 (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.Phe124Leu (c.370T>C)?

AlphaMissense predicts likely pathogenic (score 0.9174) — an in-silico prediction, not a clinical call.

ITK p.Phe124Leu

c.370T>C · rs2480559781 · VCV2004774

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9174 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

lymphoproliferative syndrome 1

Computational evidence

Protein change
AlphaMissense	0.9174	likely pathogenic
REVEL	0.745	pathogenic-leaning
SaProt	LLR -4.76	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 2, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 63 kb · p 2.1e-06 · regional, not allelic
Overall
CADD	26.2	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.Phe124Leu
Coding: c.370T>C
MANE Select: NM_005546
dbSNP: rs2480559781
Type: single nucleotide variant
Location: chr5:157214235 (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

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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
ITK p.Ala525Thr Uncertain significance ★★ ⚠ same condition
ITK p.Ala583Val 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-phe124leu (accessed [today's date]).

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