# NM_005546.4(ITK):c.681G>A (p.Val227=)

https://sugi.bio/variant/itk-p-val227

## Summary

**ITK p.Val227= (c.681G>A)** is classified **Likely benign** in ITK (ClinVar, Single submitter, 2 submitters; last evaluated 2026-01-17). Ultra-rare (popmax 0.0166%, mid); Associated with lymphoproliferative syndrome 1.

**At a glance:** Likely benign · review: Single submitter · rsID rs760264249 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0166%, mid)

## 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.Val227= |
| Coding change (HGVS c.) | c.681G>A |
| MANE Select transcript | [NM_005546](https://www.ncbi.nlm.nih.gov/nuccore/NM_005546) |
| dbSNP | [rs760264249](https://www.ncbi.nlm.nih.gov/snp/rs760264249/) |
| Variant type | single nucleotide variant |
| Location | chr5:157228329-157228329 (GRCh38) |
| ClinVar | [VCV2726271](https://www.ncbi.nlm.nih.gov/clinvar/variation/2726271/) |

**All HGVS expressions:** `LRG_189:g.52433G>A`, `LRG_189t1:c.681G>A`, `NC_000005.10:g.157228329G>A`, `NC_000005.9:g.156655339G>A`, `NG_016276.1:g.52433G>A`, `NM_005546.4:c.681G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.20) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.551, GERP -2.3, phastCons 0.992 — weakly conserved position
- CADD: **PHRED 6.427**. 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 deltas (raw): acceptor loss **0.20**, donor loss **0.12**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 33 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.0166%** (mid) · FAF95 0.00115% · FAF99 0.000976% · 1/6,028 in the highest group · 25/1,606,250 alleles overall — ultra-rare (popmax 0.0166%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0166% | 6,028 |
| Remaining individuals (not grpmax-eligible) | 0.00321% | 31,121 |
| European (non-Finnish) | 0.00179% | 55,861 |
| Admixed American | 0.00167% | 60,002 |

*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 **227** lies in the sh3 domain; a β-strand.

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.Val227= falls in the sh3 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 Single submitter *(criteria provided, single submitter)*, last evaluated 2026-01-17.

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

**Submission history:** 2 submissions (2019–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-03-12 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-17 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Lymphoproliferative syndrome 1, ITK-related disorder, ITK-related condition.

## Similar variants {#similar}

Related ITK variant pages (same residue, condition, or type): [ITK p.Val227Met](/variant/itk-p-val227met), [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 2026-10-06); 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 2026-10-14); 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 2726271). 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.*