Is ITK p.Ala140Thr (c.418G>A) pathogenic?

ITK p.Ala140Thr (c.418G>A) is classified Uncertain significance in ITK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-11). AlphaMissense: likely pathogenic (0.6595); Very rare (popmax 0.000254%, nfe).

How common is ITK p.Ala140Thr (c.418G>A) in the general population?

ITK p.Ala140Thr (c.418G>A) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about ITK p.Ala140Thr (c.418G>A)?

AlphaMissense predicts likely pathogenic (score 0.6595) — an in-silico prediction, not a clinical call.

ITK p.Ala140Thr

c.418G>A · VCV4541080

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6595 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6595	likely pathogenic
REVEL	0.818	moderately pathogenic-leaning
SaProt	LLR -8.56	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 63 kb · p 2.1e-06 · regional, not allelic
Overall
CADD	25.2	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 0.000254% European (non-Finnish) · 3/1,179,052 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000274% 4/1,460,844 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,478
European (non-Finnish)grpmax	0.000254%	393,017

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.Ala140Thr
Coding: c.418G>A
MANE Select: NM_005546
Type: single nucleotide variant
Location: chr5:157214283 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.82 · 37 PDB

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

Similar variants

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
ITK p.Ala471Thr Uncertain significance ★★ ⚠ same type
ITK p.Ala525Thr 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-ala140thr (accessed [today's date]).

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