# NM_004304.5(ALK):c.3734T>G (p.Phe1245Cys)

https://sugi.bio/variant/alk-p-phe1245cys

## Summary

**ALK p.Phe1245Cys (c.3734T>G)** is classified **Pathogenic** in ALK (ClinVar, No assertion criteria, 2 submitters; last evaluated 2015-10-07). AlphaMissense: likely pathogenic (0.9975); Absent from gnomAD v4.1; Associated with neuroblastoma, susceptibility to, 3.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs863225283 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ALK gene that is reported as disease-causing, but on limited review, submitted by 2 submitters, and is linked to neuroblastoma, susceptibility to, 3.

*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.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0027831/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ALK](https://sugi.bio/atlas/gene/ALK/) |
| Protein change (HGVS p.) | p.Phe1245Cys |
| Coding change (HGVS c.) | c.3734T>G |
| MANE Select transcript | [NM_004304](https://www.ncbi.nlm.nih.gov/nuccore/NM_004304) |
| dbSNP | [rs863225283](https://www.ncbi.nlm.nih.gov/snp/rs863225283/) |
| Variant type | single nucleotide variant |
| Location | chr2:29213993-29213993 (GRCh38) |
| ClinVar | [VCV217856](https://www.ncbi.nlm.nih.gov/clinvar/variation/217856/) |

**All HGVS expressions:** `LRG_488:g.712574T>G`, `NC_000002.11:g.29436859A>C`, `NC_000002.12:g.29213993A>C`, `NG_009445.1:g.712574T>G`, `NM_001353765.2:c.530T>G`, `NM_004304.5:c.3734T>G`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9975) — concordant with the pathogenic call
- REVEL 0.927 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -9.23 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- Conservation: phyloP 11.264, GERP 2, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 5%** most-pathogenic-predicted substitutions in ALK (of 9,451 modeled).
- CADD: **PHRED 32.0**. 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 0.59** across the covering region of the MANE Select transcript (29,197,621–29,214,059), spanning 16,438 bp. Chi-square p 1.6e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- 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}

**ALK** population constraint: LOEUF 0.562, pLI 3.8217e-06, missense-Z 0.95723; ClinGen dosage — haploinsufficiency 0, triplosensitivity 0 (0–3 scale). *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):

- **neuroblastoma, susceptibility to, 3** — Definitive (AD)

## Protein context {#protein}

Residue **1245** lies in a UniProt-annotated variant site (in nblst3; somatic mutation); the protein kinase domain.

AlphaFold model confidence (whole protein): pLDDT 68.26, 20% of residues very-high.

**79 experimental structure(s)** (PDB): [2KUP](https://www.rcsb.org/structure/2KUP), [2KUQ](https://www.rcsb.org/structure/2KUQ), [2XB7](https://www.rcsb.org/structure/2XB7), [2XBA](https://www.rcsb.org/structure/2XBA), [2XP2](https://www.rcsb.org/structure/2XP2), [2YFX](https://www.rcsb.org/structure/2YFX) — incl. mutant structure 2YFX.

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

*Describes the biological roles of ALK (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:** ALK's established molecular role includes protein tyrosine kinase activity. p.Phe1245Cys falls in the protein kinase domain. In Reactome, ALK is annotated in disease pathway(s) including **ALK mutants bind TKIs**, **ASP-3026-resistant ALK mutants**.

**Disease mechanism (Reactome):** ALK loss or alteration is curated in [ALK mutants bind TKIs](https://reactome.org/content/detail/R-HSA-9700645), [ASP-3026-resistant ALK mutants](https://reactome.org/content/detail/R-HSA-9717264), [NVP-TAE684-resistant ALK mutants](https://reactome.org/content/detail/R-HSA-9717301).

### Pathways affected {#pathways}

ALK participates in **11 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [ALK mutants bind TKIs](https://reactome.org/content/detail/R-HSA-9700645) | curated |
| ⚕ [ASP-3026-resistant ALK mutants](https://reactome.org/content/detail/R-HSA-9717264) | curated |
| ⚕ [NVP-TAE684-resistant ALK mutants](https://reactome.org/content/detail/R-HSA-9717301) | curated |
| ⚕ [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370) | curated |
| ⚕ [alectinib-resistant ALK mutants](https://reactome.org/content/detail/R-HSA-9717316) | curated |
| ⚕ [brigatinib-resistant ALK mutants](https://reactome.org/content/detail/R-HSA-9717319) | curated |
| ⚕ [ceritinib-resistant ALK mutants](https://reactome.org/content/detail/R-HSA-9717323) | curated |
| ⚕ [crizotinib-resistant ALK mutants](https://reactome.org/content/detail/R-HSA-9717326) | curated |
| ⚕ [lorlatinib-resistant ALK mutants](https://reactome.org/content/detail/R-HSA-9717329) | curated |
| [MDK and PTN in ALK signaling](https://reactome.org/content/detail/R-HSA-9851151) | electronic |
| [Signaling by ALK](https://reactome.org/content/detail/R-HSA-201556) | electronic |

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

**Molecular function:** protein tyrosine kinase activity, transmembrane receptor protein tyrosine kinase activity, heparin binding, receptor signaling protein tyrosine kinase activator activity, identical protein binding.

**Biological process:** cell surface receptor protein tyrosine kinase signaling pathway, phosphorylation, peptidyl-tyrosine autophosphorylation, protein autophosphorylation.

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2015-10-07.

**Submitter consensus:** unanimous (1/1 Pathogenic).

**Submission history:** 2 submissions (2015–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Pathogenic | no assertion criteria provided | clinical testing | 2015-10-07 |
| Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital |  | criteria provided, single submitter | clinical testing | 2025-05-05 |

## Associated conditions {#conditions}

[neuroblastoma, susceptibility to, 3](https://sugi.bio/atlas/disease/neuroblastoma-susceptibility-to-3/).

**Reported phenotype names (ClinVar):** Neuroblastoma, susceptibility to, 3, Neuroblastoma, ALK-Related Neuroblastic Tumor Susceptibility.

## Same-residue context {#hotspot}

Residue **1245** carries **3 other pathogenic ClinVar variants** — a recurrently-mutated position: [ALK p.Phe1245Ile](/variant/alk-p-phe1245ile), [ALK p.Phe1245Leu](/variant/alk-p-phe1245leu), [ALK p.Phe1245Val](/variant/alk-p-phe1245val). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Cancer therapy associations (CIViC) {#civic}

Curated clinical evidence for this variant from CIViC (profile *F1245C*):

| Disease | Therapies | Type | Level | Significance |
| --- | --- | --- | --- | --- |
| Cancer | Crizotinib | Predictive | D | Resistance |
| Neuroblastoma | Lorlatinib | Predictive | D | Sensitivity/Response |
| Neuroblastoma | Crizotinib | Predictive | C | Resistance |
| Lung Non-small Cell Carcinoma | Ceritinib | Predictive | C | Sensitivity/Response |
| Lung Non-small Cell Carcinoma | Crizotinib | Predictive | C | Resistance |
*CIViC evidence levels A–E (A strongest). Therapy associations are context-specific — not a treatment recommendation.*

## Similar variants {#similar}

Related ALK variant pages (same residue, condition, or type): [ALK p.Phe1245Val](/variant/alk-p-phe1245val), [ALK p.Phe1245Ile](/variant/alk-p-phe1245ile), [ALK p.Phe1245Leu](/variant/alk-p-phe1245leu), [ALK p.Arg1275Gln](/variant/alk-p-arg1275gln), [ALK c.1154+5G>A](/variant/alk-c-1154-plus-5g-a), [ALK c.1155-3C>T](/variant/alk-c-1155-minus-3c-t), [ALK c.1282+3A>G](/variant/alk-c-1282-plus-3a-g), [ALK c.1414+1G>A](/variant/alk-c-1414-plus-1g-a).

### 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 217856). 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.*