# NM_005546.4(ITK):c.1518C>T (p.Phe506=)

https://sugi.bio/variant/itk-p-phe506

## Summary

**ITK p.Phe506= (c.1518C>T)** is classified **Likely benign** in ITK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-23). Ultra-rare (popmax 0.0533%, amr); Associated with lymphoproliferative syndrome 1.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs755630347 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0533%, amr)

## For patients & families {#patients}

This is a change in the ITK gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to lymphoproliferative syndrome 1.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Childhood |
| Diagnostic panels | ITK is a diagnostic-grade gene on 4 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017979/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ITK](https://sugi.bio/atlas/gene/ITK/) |
| Protein change (HGVS p.) | p.Phe506= |
| Coding change (HGVS c.) | c.1518C>T |
| MANE Select transcript | [NM_005546](https://www.ncbi.nlm.nih.gov/nuccore/NM_005546) |
| dbSNP | [rs755630347](https://www.ncbi.nlm.nih.gov/snp/rs755630347/) |
| Variant type | single nucleotide variant |
| Location | chr5:157245884-157245884 (GRCh38) |
| ClinVar | [VCV1136344](https://www.ncbi.nlm.nih.gov/clinvar/variation/1136344/) |

**All HGVS expressions:** `LRG_189:g.69988C>T`, `NC_000005.10:g.157245884C>T`, `NC_000005.9:g.156672894C>T`, `NG_016276.1:g.69988C>T`, `NM_005546.4:c.1518C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -10.257, GERP -3.94 — fast-evolving / accelerated position
- CADD: **PHRED 1.316**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.31 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0533%** (amr) · FAF95 0.0387% · FAF99 0.0339% · 32/60,010 in the highest group · 48/1,613,368 alleles overall — ultra-rare (popmax 0.0533%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0533% | 1,875 |
| African / African-American | 0.00133% | 74,942 |
| European (non-Finnish) | 0.00119% | 84,239 |
| South Asian | 0.0011% | 91,078 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**ITK** population constraint: LOEUF 0.644, pLI 0.0012917, missense-Z 2.3278. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **lymphoproliferative syndrome 1** — Definitive (AR)

## Protein context {#protein}

Residue **506** lies in the protein kinase domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 84.82, 52% of residues very-high.

**37 experimental structure(s)** (PDB): [1SM2](https://www.rcsb.org/structure/1SM2), [1SNU](https://www.rcsb.org/structure/1SNU), [1SNX](https://www.rcsb.org/structure/1SNX), [2E6I](https://www.rcsb.org/structure/2E6I), [2LMJ](https://www.rcsb.org/structure/2LMJ), [2YUQ](https://www.rcsb.org/structure/2YUQ) — incl. mutant structure 3T9T.

## What this gene does {#gene-function}

*Describes the biological roles of ITK (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** ITK's established molecular role includes non-membrane spanning protein tyrosine kinase activity. p.Phe506= falls in the protein kinase domain.


### Pathways affected {#pathways}

ITK participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Generation of second messenger molecules](https://reactome.org/content/detail/R-HSA-202433) | curated |
| [FCERI mediated Ca+2 mobilization](https://reactome.org/content/detail/R-HSA-2871809) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** non-membrane spanning protein tyrosine kinase activity.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-23.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-23 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-01 |

## Associated conditions {#conditions}

[lymphoproliferative syndrome 1](https://sugi.bio/atlas/disease/lymphoproliferative-syndrome-1/).

**Reported phenotype names (ClinVar):** Lymphoproliferative syndrome 1, not provided, none provided.

## Similar variants {#similar}

Related ITK variant pages (same residue, condition, or type): [ITK p.Phe506Leu](/variant/itk-p-phe506leu), [ITK c.851+5G>A](/variant/itk-c-851-plus-5g-a), [ITK p.Ala191Thr](/variant/itk-p-ala191thr), [ITK p.Ala261Thr](/variant/itk-p-ala261thr), [ITK p.Ala308Ser](/variant/itk-p-ala308ser), [ITK p.Ala345Val](/variant/itk-p-ala345val), [ITK p.Ala471Thr](/variant/itk-p-ala471thr), [ITK p.Ala525Thr](/variant/itk-p-ala525thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1136344). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*