Is ITK p.Arg49Cys (c.145C>T) pathogenic?

ITK p.Arg49Cys (c.145C>T) is classified Uncertain significance in ITK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-28). AlphaMissense: likely benign (0.2346); Very rare (popmax 0.00051%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ITK p.Arg49Cys (c.145C>T)?

ITK p.Arg49Cys (c.145C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ITK p.Arg49Cys (c.145C>T) in the general population?

ITK p.Arg49Cys (c.145C>T) is very rare (popmax 0.00051%, nfe) (gnomAD).

What do computational predictors say about ITK p.Arg49Cys (c.145C>T)?

AlphaMissense predicts likely benign (score 0.2346) — an in-silico prediction, not a clinical call.

ITK p.Arg49Cys

c.145C>T · VCV4040331

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2346 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00051%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2346	likely benign
REVEL	0.681	pathogenic-leaning
SaProt	LLR -13.01	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.1, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 63 kb · p 2.1e-06 · regional, not allelic
Overall
CADD	28.6	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 0.00051% European (non-Finnish) · 6/1,177,544 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000411% 6/1,459,072 alleles · very rare

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.Arg49Cys
Coding: c.145C>T
MANE Select: NM_005546
Type: single nucleotide variant
Location: chr5:157208895 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.82 · 37 PDB
Residue 49: the ph domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ITK p.Arg49His Uncertain significance ★ ⚠ same residue
ITK p.Ala308Ser Uncertain significance ★★ ⚠ same condition
ITK p.Arg451Trp Uncertain significance ★★ ⚠ same condition
ITK p.Arg602Trp Uncertain significance ★★ ⚠ same condition
ITK p.Glu196Gln Uncertain significance ★★ ⚠ same condition
ITK p.His378Arg Uncertain significance ★★ ⚠ same condition
ITK p.His586Asp Uncertain significance ★★ ⚠ same condition
ITK p.Ile590Met 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-arg49cys (accessed [today's date]).

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