Is DCTN1 p.Arg669Cys (c.2005C>T) pathogenic?

DCTN1 p.Arg669Cys (c.2005C>T) is classified Uncertain significance in DCTN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-11). AlphaMissense: likely benign (0.183); Very rare (popmax 0.00483%, nfe); Associated with amyotrophic lateral sclerosis type 1.

What condition is associated with DCTN1 p.Arg669Cys (c.2005C>T)?

DCTN1 p.Arg669Cys (c.2005C>T) is associated with amyotrophic lateral sclerosis type 1, Perry syndrome, neuronopathy, distal hereditary motor, type 7B (ClinVar).

How common is DCTN1 p.Arg669Cys (c.2005C>T) in the general population?

DCTN1 p.Arg669Cys (c.2005C>T) is very rare (popmax 0.00483%, nfe) (gnomAD).

What do computational predictors say about DCTN1 p.Arg669Cys (c.2005C>T)?

AlphaMissense predicts likely benign (score 0.183) — an in-silico prediction, not a clinical call.

DCTN1 p.Arg669Cys

c.2005C>T · rs150746209 · VCV536162

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.183 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00483%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

amyotrophic lateral sclerosis type 1

Computational evidence

Protein change
AlphaMissense	0.183	likely benign
REVEL	0.463	indeterminate
SaProt	LLR -10.17	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 2.4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 3,200 bp · p 0.5 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00483% European (non-Finnish) · 57/1,180,036 alleles

Filtering AF 0.00377% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00345%

Overall 0.0039% 63/1,614,094 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00483%	20,702
South Asian	0.00329%	30,365
East Asian	0.00223%	44,900
Finnishnot grpmax-eligible	0.00156%	64,038
African / African-American	0.00133%	74,920

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: DCTN1
Protein: p.Arg669Cys
Coding: c.2005C>T
MANE Select: NM_004082
dbSNP: rs150746209
Type: single nucleotide variant
Location: chr2:74367981 (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 type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Perry syndrome neuronopathy, distal hereditary motor, type 7B

Similar variants

DCTN1 p.Arg669His Uncertain significance ★★ ⚠ same residue
DCTN1 p.Arg669Leu Uncertain significance ★★ ⚠ same residue
DCTN1 c.279+1G>T Pathogenic/Likely pathogenic ★★ same condition
DCTN1 p.Gln93His Pathogenic/Likely pathogenic ★★ same condition
DCTN1 p.Gly71Glu Pathogenic ★★ same condition
DCTN1 p.Tyr78His Likely pathogenic ★★ same condition
DCTN1 c.1128-3C>G Uncertain significance ★★ same condition
DCTN1 c.1288-10C>G Uncertain significance ★★ 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-arg669cys (accessed [today's date]).

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