Is ITK p.Arg451Gln (c.1352G>A) pathogenic?

ITK p.Arg451Gln (c.1352G>A) is classified Uncertain significance in ITK (ClinVar, Single submitter, 1 submitter; last evaluated 2019-09-06). AlphaMissense: likely benign (0.1332); Very rare (popmax 0.004%, afr).

How common is ITK p.Arg451Gln (c.1352G>A) in the general population?

ITK p.Arg451Gln (c.1352G>A) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about ITK p.Arg451Gln (c.1352G>A)?

AlphaMissense predicts likely benign (score 0.1332) — an in-silico prediction, not a clinical call.

ITK p.Arg451Gln

c.1352G>A · VCV4972835

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1332 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1332	likely benign
REVEL	0.205	benign-leaning
SaProt	LLR -8.28	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
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	25.9	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 0.004% African / African-American · 3/75,016 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000494%

Overall 0.000991% 16/1,613,906 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	25,005
Finnishnot grpmax-eligible	0.00156%	64,010
European (non-Finnish)	0.00102%	98,323

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.Arg451Gln
Coding: c.1352G>A
MANE Select: NM_005546
Type: single nucleotide variant
Location: chr5:157244381 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.82 · 37 PDB
Residue 451: a UniProt-annotated variant site (in a gastric adenocarcinoma sample; somatic mutation); the protein kinase domain; a turn

Full ITK gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ITK p.Arg451Trp Uncertain significance ★★ same residue
ITK p.Arg451= Likely benign ★ same residue
ITK p.Arg562Ter Pathogenic/Likely pathogenic ★★ same type
ITK c.851+5G>A Uncertain significance ★★ same type
ITK p.Ala191Thr Uncertain significance ★★ ⚠ same type
ITK p.Ala261Thr Uncertain significance ★★ ⚠ same type
ITK p.Ala308Ser Uncertain significance ★★ ⚠ same type
ITK p.Ala345Val Uncertain significance ★★ ⚠ same type

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-arg451gln (accessed [today's date]).

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