Is DCTN1 p.Arg148Trp (c.442C>T) pathogenic?

DCTN1 p.Arg148Trp (c.442C>T) is classified Conflicting classifications of pathogenicity in DCTN1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-02-05). AlphaMissense: ambiguous (0.5061); Very rare (popmax 0.00746%, nfe); Associated with Perry syndrome.

What condition is associated with DCTN1 p.Arg148Trp (c.442C>T)?

DCTN1 p.Arg148Trp (c.442C>T) is associated with Perry syndrome, amyotrophic lateral sclerosis type 1, neuronopathy, distal hereditary motor, type 7B (ClinVar).

How common is DCTN1 p.Arg148Trp (c.442C>T) in the general population?

DCTN1 p.Arg148Trp (c.442C>T) is very rare (popmax 0.00746%, nfe) (gnomAD).

How is Perry syndrome inherited?

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

What do computational predictors say about DCTN1 p.Arg148Trp (c.442C>T)?

AlphaMissense predicts ambiguous (score 0.5061) — an in-silico prediction, not a clinical call.

DCTN1 p.Arg148Trp

c.442C>T · rs148810193 · VCV447238

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.5061 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00746%, nfe)

Conditions

Perry syndrome

Computational evidence

Protein change
AlphaMissense	0.5061	ambiguous
REVEL	0.309	indeterminate
SaProt	LLR -10.17	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 6,503 bp · p 0.9 · regional, not allelic
Overall
CADD	31.0	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 0.00746% European (non-Finnish) · 88/1,179,994 alleles

Filtering AF 0.00615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00573%

Overall 0.00626% 101/1,614,012 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0128%	7,813
European (non-Finnish)grpmax	0.00746%	13,409
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
South Asian	0.0022%	45,539
Finnishnot grpmax-eligible	0.00156%	63,948
African / African-American	0.00133%	75,004

Remaining individuals shows a higher raw frequency than the grpmax group above it. 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.

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.Arg148Trp
Coding: c.442C>T
MANE Select: NM_004082
dbSNP: rs148810193
Type: single nucleotide variant
Location: chr2:74372939 (GRCh38)
Gene constraint: LOEUF 0.448 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.43 · 13 PDB
Residue 148: the 'disordered' region

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

Disease context

Perry syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: amyotrophic lateral sclerosis type 1 neuronopathy, distal hereditary motor, type 7B

For Perry syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

DCTN1 p.Arg148Gln Uncertain significance ★★ ⚠ same residue
DCTN1 p.Arg148Gly 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-arg148trp (accessed [today's date]).

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