Is ITK p.Arg448His (c.1343G>A) pathogenic?

ITK p.Arg448His (c.1343G>A) is classified Uncertain significance in ITK (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.1839); Ultra-rare (popmax 0.0373%, sas); Associated with lymphoproliferative syndrome 1.

What condition is associated with ITK p.Arg448His (c.1343G>A)?

ITK p.Arg448His (c.1343G>A) is associated with lymphoproliferative syndrome 1 (ClinVar).

How common is ITK p.Arg448His (c.1343G>A) in the general population?

ITK p.Arg448His (c.1343G>A) is ultra-rare (popmax 0.0373%, sas) (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.Arg448His (c.1343G>A)?

AlphaMissense predicts likely benign (score 0.1839) — an in-silico prediction, not a clinical call.

ITK p.Arg448His

c.1343G>A · rs144735141 · VCV577129

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1839 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0373%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

lymphoproliferative syndrome 1

Computational evidence

Protein change
AlphaMissense	0.1839	likely benign
REVEL	0.559	indeterminate
SaProt	LLR -10.20	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 63 kb · p 2.1e-06 · regional, not allelic
Overall
CADD	31.0	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

Grpmax group 0.0373% South Asian · 34/91,068 alleles

Filtering AF 0.0274% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.024%

Overall 0.02% 323/1,613,778 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.04%	2,499
South Asiangrpmax	0.0373%	2,678
East Asian	0.0267%	3,739
European (non-Finnish)	0.0211%	4,739
Middle Eastern	0.0164%	6,084
African / African-American	0.00267%	37,436

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg448His
Coding: c.1343G>A
MANE Select: NM_005546
dbSNP: rs144735141
Type: single nucleotide variant
Location: chr5:157244372 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.82 · 37 PDB
Residue 448: the protein kinase domain; an α-helix

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.Arg448Cys Uncertain significance ★ ⚠ same residue
ITK p.Arg448Gly Uncertain significance ★ same residue
ITK p.Arg448Pro 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.Ala345Val 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-arg448his (accessed [today's date]).

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