Is ITK p.Val357Gly (c.1070T>G) pathogenic?

ITK p.Val357Gly (c.1070T>G) is classified Uncertain significance in ITK (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-14). AlphaMissense: likely benign (0.2169); Very rare (popmax 0.000424%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ITK p.Val357Gly (c.1070T>G)?

ITK p.Val357Gly (c.1070T>G) is associated with Inborn genetic diseases (ClinVar).

How common is ITK p.Val357Gly (c.1070T>G) in the general population?

ITK p.Val357Gly (c.1070T>G) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about ITK p.Val357Gly (c.1070T>G)?

AlphaMissense predicts likely benign (score 0.2169) — an in-silico prediction, not a clinical call.

ITK p.Val357Gly

c.1070T>G · rs2532155175 · VCV3111650

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2169 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2169	likely benign
REVEL	0.208	benign-leaning
SaProt	LLR -10.52	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP -2.2, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 63 kb · p 2.1e-06 · regional, not allelic
Overall
CADD	21.8	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 0.000424% European (non-Finnish) · 5/1,179,916 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000342% 5/1,460,404 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.Val357Gly
Coding: c.1070T>G
MANE Select: NM_005546
dbSNP: rs2532155175
Type: single nucleotide variant
Location: chr5:157243632 (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

Disease context

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

Similar variants

ITK p.Val357Met 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-val357gly (accessed [today's date]).

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