Is ITK p.Glu309= (c.927A>G) pathogenic?

ITK p.Glu309= (c.927A>G) is classified Likely benign in ITK (ClinVar, Single submitter, 1 submitter; last evaluated 2021-03-24). Ultra-rare (popmax 0.012%, afr); Associated with lymphoproliferative syndrome 1.

What condition is associated with ITK p.Glu309= (c.927A>G)?

ITK p.Glu309= (c.927A>G) is associated with lymphoproliferative syndrome 1 (ClinVar).

How common is ITK p.Glu309= (c.927A>G) in the general population?

ITK p.Glu309= (c.927A>G) is ultra-rare (popmax 0.012%, afr) (gnomAD).

How is Combined immunodeficiency due to ITK deficiency inherited?

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

ITK p.Glu309=

c.927A>G · rs372201861 · VCV1628916

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Conditions

lymphoproliferative syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.53	GERP -3.9, phastCons 0.96
Overall
CADD	5.029	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.012% African / African-American · 9/74,916 alleles

Filtering AF 0.00624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.00062% 10/1,613,826 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,324
Admixed American	0.00167%	59,996

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.Glu309=
Coding: c.927A>G
MANE Select: NM_005546
dbSNP: rs372201861
Type: single nucleotide variant
Location: chr5:157240137 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.82 · 37 PDB
Residue 309: the sh2 domain

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.Glu309Ter Pathogenic ★ 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
ITK p.Ala525Thr 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-glu309 (accessed [today's date]).

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