Is ITK p.Arg29Cys (c.85C>T) pathogenic?

ITK p.Arg29Cys (c.85C>T) is classified Uncertain significance in ITK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-27). AlphaMissense: likely pathogenic (0.9567); Very rare (popmax 0.00446%, eas); Associated with lymphoproliferative syndrome 1.

What condition is associated with ITK p.Arg29Cys (c.85C>T)?

ITK p.Arg29Cys (c.85C>T) is associated with lymphoproliferative syndrome 1 (ClinVar).

How common is ITK p.Arg29Cys (c.85C>T) in the general population?

ITK p.Arg29Cys (c.85C>T) is very rare (popmax 0.00446%, eas) (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.Arg29Cys (c.85C>T)?

AlphaMissense predicts likely pathogenic (score 0.9567) — an in-silico prediction, not a clinical call.

ITK p.Arg29Cys

c.85C>T · rs201513154 · VCV2417920

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9567 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

lymphoproliferative syndrome 1

Computational evidence

Protein change
AlphaMissense	0.9567	likely pathogenic
REVEL	0.93	moderately pathogenic-leaning
SaProt	LLR -14.16	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 63 kb · p 2.1e-06 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00446% East Asian · 2/44,882 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000867% 14/1,613,960 alleles · very rare exomes 10/1,461,672 · genomes 4/152,288 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,441
South Asian	0.0022%	45,540
Remaining individualsnot grpmax-eligible	0.0016%	62,496
African / African-American	0.00133%	75,024
European (non-Finnish)	0.000678%	147,483

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.Arg29Cys
Coding: c.85C>T
MANE Select: NM_005546
dbSNP: rs201513154
Type: single nucleotide variant
Location: chr5:157181062 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.82 · 37 PDB
Residue 29: the ph 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.Arg29= Likely benign ★★ same residue
ITK p.Arg29His Likely 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

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-arg29cys (accessed [today's date]).

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