Is ITK p.Pro187Ser (c.559C>T) pathogenic?

ITK p.Pro187Ser (c.559C>T) is classified Uncertain significance in ITK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-25). AlphaMissense: likely benign (0.0875); Very rare (popmax 0.005%, amr); Associated with autoinflammatory syndrome.

What condition is associated with ITK p.Pro187Ser (c.559C>T)?

ITK p.Pro187Ser (c.559C>T) is associated with autoinflammatory syndrome (ClinVar).

How common is ITK p.Pro187Ser (c.559C>T) in the general population?

ITK p.Pro187Ser (c.559C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about ITK p.Pro187Ser (c.559C>T)?

AlphaMissense predicts likely benign (score 0.0875) — an in-silico prediction, not a clinical call.

ITK p.Pro187Ser

c.559C>T · rs1156578676 · VCV1694290

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0875 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autoinflammatory syndrome

Computational evidence

Protein change
AlphaMissense	0.0875	likely benign
REVEL	0.133	moderately benign-leaning
SaProt	LLR -4.55	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 4	GERP -0.028, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 63 kb · p 2.1e-06 · regional, not allelic
Overall
CADD	18.75	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 0.005% Admixed American · 3/59,968 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000929% 15/1,613,948 alleles · very rare exomes 10/1,461,872 · genomes 5/152,076 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0064%	15,621
Admixed Americangrpmax	0.005%	19,989
East Asian	0.00446%	22,438
African / African-American	0.004%	24,970
European (non-Finnish)	0.000254%	393,342

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.Pro187Ser
Coding: c.559C>T
MANE Select: NM_005546
dbSNP: rs1156578676
Type: single nucleotide variant
Location: chr5:157222926 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.82 · 37 PDB
Residue 187: the sh3 domain; a β-strand

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

Disease context

autoinflammatory syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ITK p.Arg96Pro Uncertain significance ★★ same condition
ITK p.Phe530Val Uncertain significance ★★ ⚠ same condition
ITK c.244-8G>A Benign/Likely benign ★★ same condition
ITK c.769-10A>T Benign/Likely benign ★★ same condition
ITK p.Arg193Gln Benign/Likely benign ★★ same condition
ITK p.Val587Ile Benign/Likely benign ★★ same condition
ITK c.139-6C>T Conflicting classifications of pathogenicity ★ same condition
ITK c.1792-4C>T Conflicting classifications of pathogenicity ★ 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-pro187ser (accessed [today's date]).

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