Is ITK p.Ala345Ser (c.1033G>T) pathogenic?

ITK p.Ala345Ser (c.1033G>T) is classified Uncertain significance in ITK (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-20). AlphaMissense: likely benign (0.1269); Very rare (popmax 8.48e-05%, nfe); Associated with lymphoproliferative syndrome 1.

What condition is associated with ITK p.Ala345Ser (c.1033G>T)?

ITK p.Ala345Ser (c.1033G>T) is associated with lymphoproliferative syndrome 1 (ClinVar).

How common is ITK p.Ala345Ser (c.1033G>T) in the general population?

ITK p.Ala345Ser (c.1033G>T) is very rare (popmax 8.48e-05%, 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.Ala345Ser (c.1033G>T)?

AlphaMissense predicts likely benign (score 0.1269) — an in-silico prediction, not a clinical call.

ITK p.Ala345Ser

c.1033G>T · rs1202690965 · VCV1475882

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1269 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

lymphoproliferative syndrome 1

Computational evidence

Protein change
AlphaMissense	0.1269	likely benign
REVEL	0.326	indeterminate
SaProt	LLR -6.02	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 63 kb · p 2.1e-06 · regional, not allelic
Overall
CADD	21.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,844 alleles

Overall 6.84e-05% 1/1,461,614 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.Ala345Ser
Coding: c.1033G>T
MANE Select: NM_005546
dbSNP: rs1202690965
Type: single nucleotide variant
Location: chr5:157241693 (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.Ala345Val Uncertain significance ★★ ⚠ 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.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-ala345ser (accessed [today's date]).

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