Is DCTN1 p.Leu746Pro (c.2237T>C) pathogenic?

DCTN1 p.Leu746Pro (c.2237T>C) is classified Uncertain significance in DCTN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-03-31). AlphaMissense: likely pathogenic (0.9937); Absent from gnomAD v4.1; Associated with amyotrophic lateral sclerosis.

What condition is associated with DCTN1 p.Leu746Pro (c.2237T>C)?

DCTN1 p.Leu746Pro (c.2237T>C) is associated with amyotrophic lateral sclerosis (ClinVar).

How common is DCTN1 p.Leu746Pro (c.2237T>C) in the general population?

DCTN1 p.Leu746Pro (c.2237T>C) is absent from gnomAD v4.1 (gnomAD).

How is Amyotrophic lateral sclerosis inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about DCTN1 p.Leu746Pro (c.2237T>C)?

AlphaMissense predicts likely pathogenic (score 0.9937) — an in-silico prediction, not a clinical call.

DCTN1 p.Leu746Pro

c.2237T>C · rs1674497225 · VCV873285

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9937 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

amyotrophic lateral sclerosis

Computational evidence

Protein change
AlphaMissense	0.9937	likely pathogenic · top 4% in DCTN1
REVEL	0.87	moderately pathogenic-leaning
SaProt	LLR -12.81	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 3,200 bp · p 0.5 · regional, not allelic
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DCTN1
Protein: p.Leu746Pro
Coding: c.2237T>C
MANE Select: NM_004082
dbSNP: rs1674497225
Type: single nucleotide variant
Location: chr2:74367368 (GRCh38)
Gene constraint: LOEUF 0.448 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.43 · 13 PDB

Full DCTN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

amyotrophic lateral sclerosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Amyotrophic lateral sclerosis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: Adult
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

DCTN1 p.Leu746= Likely benign ★★ same residue
DCTN1 p.Asp226Asn Uncertain significance ★★ ⚠ same condition
DCTN1 p.Asp748Glu Uncertain significance ★★ ⚠ same condition
DCTN1 p.Ile780Thr Uncertain significance ★★ ⚠ same condition
DCTN1 p.Thr43Ala Uncertain significance ★★ ⚠ same condition
DCTN1 p.Ile622Phe Likely pathogenic ★ same condition
DCTN1 c.279+1G>C Conflicting classifications of pathogenicity ★ same condition
DCTN1 p.Arg32Cys Conflicting classifications of pathogenicity ★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/dctn1-p-leu746pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown