Is ITK p.His217= (c.651T>C) pathogenic?

ITK p.His217= (c.651T>C) is classified Likely benign in ITK (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-20). Absent from gnomAD v4.1; Associated with lymphoproliferative syndrome 1.

What condition is associated with ITK p.His217= (c.651T>C)?

ITK p.His217= (c.651T>C) is associated with lymphoproliferative syndrome 1 (ClinVar).

How common is ITK p.His217= (c.651T>C) in the general population?

ITK p.His217= (c.651T>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.

ITK p.His217=

c.651T>C · rs2480580399 · VCV1956450

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

lymphoproliferative syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.3	GERP 0.82, phastCons 1
Overall
CADD	7.331	PHRED · no single calibrated threshold — expert panels disagree

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.His217=
Coding: c.651T>C
MANE Select: NM_005546
dbSNP: rs2480580399
Type: single nucleotide variant
Location: chr5:157228299 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.82 · 37 PDB
Residue 217: the sh3 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 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
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-his217 (accessed [today's date]).

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