# NM_004304.5(ALK):c.775C>T (p.Arg259Cys)

https://sugi.bio/variant/alk-p-arg259cys

## Summary

**ALK p.Arg259Cys (c.775C>T)** is classified **Conflicting classifications of pathogenicity** in ALK (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-23). AlphaMissense: likely pathogenic (0.6509); Ultra-rare (popmax 0.03%, amr); Associated with hereditary neoplastic syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs771593278 · 6 submitters · 2 linked conditions · AlphaMissense likely pathogenic · ultra-rare (popmax 0.03%, amr)

## For patients & families {#patients}

This is a change in the ALK gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 6 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.Arg259Cys |
| Coding change (HGVS c.) | c.775C>T |
| MANE Select transcript | [NM_004304](https://www.ncbi.nlm.nih.gov/nuccore/NM_004304) |
| dbSNP | [rs771593278](https://www.ncbi.nlm.nih.gov/snp/rs771593278/) |
| Variant type | single nucleotide variant |
| Location | chr2:29717590-29717590 (GRCh38) |
| ClinVar | [VCV404385](https://www.ncbi.nlm.nih.gov/clinvar/variation/404385/) |

**All HGVS expressions:** `LRG_488:g.208977C>T`, `LRG_488t1:c.775C>T`, `NC_000002.11:g.29940456G>A`, `NC_000002.12:g.29717590G>A`, `NG_009445.1:g.208977C>T`, `NM_004304.5:c.775C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.6509)
- REVEL 0.175 (moderately benign-leaning) — differs from AlphaMissense
- SaProt LLR -8.879 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; REVEL and SaProt do not
- Conservation: phyloP 11.817, GERP 2.59, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 27.9**. 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 1.05** across the covering region of the MANE Select transcript (29,251,141–29,920,659), spanning 669,518 bp. Chi-square p 0.12. 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 (gnomAD v4.1): grpmax **0.03%** (amr) · FAF95 0.0194% · FAF99 0.016% · 18/60,004 in the highest group · 34/1,613,862 alleles overall — ultra-rare (popmax 0.03%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.03% | 3,334 |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,622 |
| African / African-American | 0.00267% | 37,449 |
| European (non-Finnish) | 0.000848% | 117,990 |

*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}


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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-12-23.

**Submitter consensus:** conflicting (3 Uncertain significance, 2 Likely benign).

**Submission history:** 6 submissions (2021–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Sema4, Sema4 | Likely benign | criteria provided, single submitter | curation | 2021-08-19 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-23 |
| Baylor Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-10-15 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-05-23 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-02-12 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |

## 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, not provided, Malignant tumor of urinary bladder, Tumor predisposition, Neoplastic Syndromes, Hereditary, Hereditary Cancer Syndrome, Hereditary neoplastic syndrome, none provided, ALK-Related Neuroblastic Tumor Susceptibility.

## Similar variants {#similar}

Related ALK variant pages (same residue, condition, or type): [ALK p.Arg259Gly](/variant/alk-p-arg259gly), [ALK p.Arg259His](/variant/alk-p-arg259his), [ALK p.Arg259Leu](/variant/alk-p-arg259leu), [ALK p.Arg259Pro](/variant/alk-p-arg259pro), [ALK p.Arg259Ser](/variant/alk-p-arg259ser), [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).

### 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 404385). 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.*