# NM_005546.4(ITK):c.1394A>C (p.Asp465Ala)

https://sugi.bio/variant/itk-p-asp465ala

## Summary

**ITK p.Asp465Ala (c.1394A>C)** is classified **Uncertain significance** in ITK (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-21). AlphaMissense: likely pathogenic (0.9453); Absent from gnomAD v4.1; Associated with lymphoproliferative syndrome 1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1754980034 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ITK gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, 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.Asp465Ala |
| Coding change (HGVS c.) | c.1394A>C |
| MANE Select transcript | [NM_005546](https://www.ncbi.nlm.nih.gov/nuccore/NM_005546) |
| dbSNP | [rs1754980034](https://www.ncbi.nlm.nih.gov/snp/rs1754980034/) |
| Variant type | single nucleotide variant |
| Location | chr5:157244423-157244423 (GRCh38) |
| ClinVar | [VCV840148](https://www.ncbi.nlm.nih.gov/clinvar/variation/840148/) |

**All HGVS expressions:** `LRG_189:g.68527A>C`, `LRG_189t1:c.1394A>C`, `NC_000005.10:g.157244423A>C`, `NC_000005.9:g.156671433A>C`, `NG_016276.1:g.68527A>C`, `NM_005546.4:c.1394A>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9453)
- REVEL 0.71 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -11.298 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.228, GERP 1.97, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 28.3**. 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.*
- Regional missense constraint: **o/e 0.80** across the covering region of the MANE Select transcript (157,180,978–157,244,437), spanning 63,459 bp. Chi-square p 2.1e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (A>G, Δ0.25 donor 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **465** 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.Asp465Ala 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-07-21.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-07-21 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Lymphoproliferative syndrome 1.

## Similar variants {#similar}

Related ITK variant pages (same residue, condition, or type): [ITK p.Asp465Asn](/variant/itk-p-asp465asn), [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 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 840148). 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.*