# NM_004082.5(DCTN1):c.5C>T (p.Ala2Val)

https://sugi.bio/variant/dctn1-p-ala2val

## Summary

**DCTN1 p.Ala2Val (c.5C>T)** is classified **Uncertain significance** in DCTN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-08). AlphaMissense: ambiguous (0.4291); Very rare (popmax 0.000169%, nfe); Associated with Perry syndrome.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1675439973 · 1 submitter · 3 linked conditions · AlphaMissense ambiguous · very rare (popmax 0.000169%, nfe)

## For patients & families {#patients}

This is a change in the DCTN1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Perry 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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adult |
| Diagnostic panels | DCTN1 is a diagnostic-grade gene on 7 Genomics England panels |

**Commonly reported features of Perry syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Depression — Very frequent (99-80%)
- Apathy — Very frequent (99-80%)
- Parkinsonism — Very frequent (99-80%)
- Tremor — Very frequent (99-80%)
- Weight loss — Very frequent (99-80%)
- Abnormality of extrapyramidal motor function — Very frequent (99-80%)
- Sleep abnormality — Very frequent (99-80%)
- Central hypoventilation — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010453/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DCTN1](https://sugi.bio/atlas/gene/DCTN1/) |
| Protein change (HGVS p.) | p.Ala2Val |
| Coding change (HGVS c.) | c.5C>T |
| MANE Select transcript | [NM_004082](https://www.ncbi.nlm.nih.gov/nuccore/NM_004082) |
| dbSNP | [rs1675439973](https://www.ncbi.nlm.nih.gov/snp/rs1675439973/) |
| Variant type | single nucleotide variant |
| Location | chr2:74380033-74380033 (GRCh38) |
| ClinVar | [VCV1492087](https://www.ncbi.nlm.nih.gov/clinvar/variation/1492087/) |

**All HGVS expressions:** `LRG_237:g.17055C>T`, `NC_000002.11:g.74607160G>A`, `NC_000002.12:g.74380033G>A`, `NG_008735.2:g.17055C>T`, `NM_001135040.3:c.5C>T`, `NM_001190836.2:c.-18-1788C>T`, `NM_001190837.2:c.5C>T`, `NM_001378991.1:c.-18-1788C>T`, `NM_001378992.1:c.-18-1788C>T`, `NM_004082.5:c.5C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL make no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.4291) — no call either way
- REVEL 0.298 (indeterminate)
- SaProt LLR -8.399 (tolerated)
- Conservation: phyloP 11.879, GERP 2.77, phastCons 1 — highly conserved
- CADD: **PHRED 25.8**. 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 0.97** across the covering region of the MANE Select transcript (74,378,176–74,380,037), spanning 1,861 bp. Chi-square p 0.85. 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 **0.000169%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,180,010 in the highest group · 3/1,461,836 alleles overall — very rare (popmax 0.000169%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,508 |
| European (non-Finnish) (grpmax) | 0.000169% | 590,005 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**DCTN1** population constraint: LOEUF 0.448, pLI 0.99981, missense-Z 2.5036. *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):

- **amyotrophic lateral sclerosis** — Moderate (AD)

## Protein context {#protein}

Residue **2** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 77.43, 28% of residues very-high.

**13 experimental structure(s)** (PDB): [1TXQ](https://www.rcsb.org/structure/1TXQ), [2COY](https://www.rcsb.org/structure/2COY), [2HKN](https://www.rcsb.org/structure/2HKN), [2HKQ](https://www.rcsb.org/structure/2HKQ), [2HL3](https://www.rcsb.org/structure/2HL3), [2HL5](https://www.rcsb.org/structure/2HL5) — incl. mutant structure 2HL3.

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

*Describes the biological roles of DCTN1 (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:** DCTN1's established molecular role includes microtubule binding. p.Ala2Val falls in the disordered region. In Reactome, DCTN1 is annotated in disease pathway(s) including **Signaling by ALK fusions and activated point mutants**.

**Disease mechanism (Reactome):** DCTN1 loss or alteration is curated in [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370).

### Pathways affected {#pathways}

DCTN1 participates in **14 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370) | curated |
| [COPI-independent Golgi-to-ER retrograde traffic](https://reactome.org/content/detail/R-HSA-6811436) | curated |
| [COPI-mediated anterograde transport](https://reactome.org/content/detail/R-HSA-6807878) | curated |
| [HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand](https://reactome.org/content/detail/R-HSA-3371497) | curated |
| [MHC class II antigen presentation](https://reactome.org/content/detail/R-HSA-2132295) | curated |
| [Processing of antigen in germinal center B cells](https://reactome.org/content/detail/R-HSA-9979719) | curated |
| [XBP1(S) activates chaperone genes](https://reactome.org/content/detail/R-HSA-381038) | curated |
| [AURKA Activation by TPX2](https://reactome.org/content/detail/R-HSA-8854518) | other |
| [Anchoring of the basal body to the plasma membrane](https://reactome.org/content/detail/R-HSA-5620912) | other |
| [Loss of Nlp from mitotic centrosomes](https://reactome.org/content/detail/R-HSA-380259) | other |
| [Loss of proteins required for interphase microtubule organization from the centrosome](https://reactome.org/content/detail/R-HSA-380284) | other |
| [Recruitment of NuMA to mitotic centrosomes](https://reactome.org/content/detail/R-HSA-380320) | other |
| [Recruitment of mitotic centrosome proteins and complexes](https://reactome.org/content/detail/R-HSA-380270) | other |
| [Regulation of PLK1 Activity at G2/M Transition](https://reactome.org/content/detail/R-HSA-2565942) | other |

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

**Molecular function:** microtubule binding, tubulin binding, protein kinase binding.

**Biological process:** establishment of mitotic spindle orientation, mitotic nuclear membrane disassembly, neuromuscular junction development, centriole-centriole cohesion, ventral spinal cord development, positive regulation of microtubule polymerization.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-03-08.

**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 | 2022-03-08 |

## Associated conditions {#conditions}

[Perry syndrome](https://sugi.bio/atlas/disease/perry-syndrome/), [amyotrophic lateral sclerosis type 1](https://sugi.bio/atlas/disease/amyotrophic-lateral-sclerosis-type-1/), [neuronopathy, distal hereditary motor, type 7B](https://sugi.bio/atlas/disease/neuronopathy-distal-hereditary-motor-type-7b/).

**Reported phenotype names (ClinVar):** Perry syndrome, Amyotrophic lateral sclerosis type 1, Neuronopathy, distal hereditary motor, type 7B, PARKINSONISM WITH ALVEOLAR HYPOVENTILATION AND MENTAL DEPRESSION, HMN VIIB, Distal Hereditary Motor Neuronopathy Type 7B (dHMN7B), LOWER MOTOR NEURON DISEASE, DYNACTIN TYPE, NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 14, NEURONOPATHY, DISTAL HEREDITARY MOTOR, HARDING TYPE VIIB, NEUROPATHY, DISTAL HEREDITARY MOTOR, HARDING TYPE VIIB.

## Similar variants {#similar}

Related DCTN1 variant pages (same residue, condition, or type): [DCTN1 c.279+1G>T](/variant/dctn1-c-279-plus-1g-t), [DCTN1 p.Gln93His](/variant/dctn1-p-gln93his), [DCTN1 p.Gly71Glu](/variant/dctn1-p-gly71glu), [DCTN1 p.Tyr78His](/variant/dctn1-p-tyr78his), [DCTN1 c.1128-3C>G](/variant/dctn1-c-1128-minus-3c-g), [DCTN1 c.1288-10C>G](/variant/dctn1-c-1288-minus-10c-g), [DCTN1 c.2185-3C>T](/variant/dctn1-c-2185-minus-3c-t), [DCTN1 c.33+3A>G](/variant/dctn1-c-33-plus-3a-g).

### 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 1492087). 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.*