# NM_004304.5(ALK):c.4186G>T (p.Ala1396Ser)

https://sugi.bio/variant/alk-p-ala1396ser

## Summary

**ALK p.Ala1396Ser (c.4186G>T)** is classified **Uncertain significance** in ALK (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-03). AlphaMissense: likely benign (0.0721); Very rare (popmax 0.00223%, eas); Associated with hereditary neoplastic syndrome.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs201768549 · 3 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the ALK gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters, and is linked to hereditary neoplastic syndrome.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 31 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019921/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.Ala1396Ser |
| Coding change (HGVS c.) | c.4186G>T |
| MANE Select transcript | [NM_004304](https://www.ncbi.nlm.nih.gov/nuccore/NM_004304) |
| dbSNP | [rs201768549](https://www.ncbi.nlm.nih.gov/snp/rs201768549/) |
| Variant type | single nucleotide variant |
| Location | chr2:29193901-29193901 (GRCh38) |
| ClinVar | [VCV3011321](https://www.ncbi.nlm.nih.gov/clinvar/variation/3011321/) |

**All HGVS expressions:** `LRG_488:g.732666G>T`, `LRG_488t1:c.4186G>T`, `NC_000002.11:g.29416767C>A`, `NC_000002.12:g.29193901C>A`, `NG_009445.1:g.732666G>T`, `NM_001353765.2:c.982G>T`, `NM_004304.4:c.4186G>T`, `NM_004304.5:c.4186G>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0721)
- REVEL 0.221 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.467 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor gain** (Δ 0.28) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 1.05, GERP 0.398, phastCons 0.488 — weakly conserved position
- CADD: **PHRED 16.5**. 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 1.10** across the covering region of the MANE Select transcript (29,193,227–29,197,620), spanning 4,393 bp. Chi-square p 0.054. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.04**, donor loss **0.00**, acceptor gain **0.28**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.04**, donor loss **0.00**, acceptor gain **0.28**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · 1/44,870 in the highest group · 1/1,461,840 alleles overall — very rare (popmax 0.00223%, eas).

*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 **1396** lies in an α-helix.

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. 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-05-03.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 3 submissions (2023–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-05-03 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-07-10 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, Neuroblastoma, susceptibility to, 3, Ovarian serous cystadenocarcinoma, Hereditary neoplastic syndrome, Hereditary Cancer Syndrome, Neoplastic Syndromes, Hereditary, Tumor predisposition, ALK-Related Neuroblastic Tumor Susceptibility.

## Similar variants {#similar}

Related ALK variant pages (same residue, condition, or type): [ALK p.Ala1396Thr](/variant/alk-p-ala1396thr), [ALK p.Ala1396Val](/variant/alk-p-ala1396val), [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), [ALK c.1414+3G>A](/variant/alk-c-1414-plus-3g-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 3011321). 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.*