Is DCTN1 p.Ala142Pro (c.424G>C) pathogenic?

DCTN1 p.Ala142Pro (c.424G>C) is classified Uncertain significance in DCTN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-19). AlphaMissense: likely benign (0.0754); Ultra-rare (popmax 0.0308%, afr); Associated with Inborn genetic diseases.

What condition is associated with DCTN1 p.Ala142Pro (c.424G>C)?

DCTN1 p.Ala142Pro (c.424G>C) is associated with Inborn genetic diseases, amyotrophic lateral sclerosis type 1, Perry syndrome (ClinVar).

How common is DCTN1 p.Ala142Pro (c.424G>C) in the general population?

DCTN1 p.Ala142Pro (c.424G>C) is ultra-rare (popmax 0.0308%, afr) (gnomAD).

What do computational predictors say about DCTN1 p.Ala142Pro (c.424G>C)?

AlphaMissense predicts likely benign (score 0.0754) — an in-silico prediction, not a clinical call.

DCTN1 p.Ala142Pro

c.424G>C · rs372096285 · VCV641178

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0754 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0308%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0754	likely benign
REVEL	0.113	moderately benign-leaning
SaProt	LLR -4.98	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 2.2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 6,503 bp · p 0.9 · regional, not allelic
Overall
CADD	21.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.0308% African / African-American · 23/74,790 alleles

Filtering AF 0.021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0178%

Overall 0.00192% 31/1,613,344 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0308%	3,252
Admixed American	0.00834%	11,994
Remaining individualsnot grpmax-eligible	0.0032%	31,222
European (non-Finnish)	8.48e-05%	1,179,748

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.Ala142Pro
Coding: c.424G>C
MANE Select: NM_004082
dbSNP: rs372096285
Type: single nucleotide variant
Location: chr2:74374331 (GRCh38)
Gene constraint: LOEUF 0.448 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.43 · 13 PDB
Residue 142: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

DCTN1 p.Ala142Val Uncertain significance ★ ⚠ same residue
DCTN1 p.Ala142= Likely benign ★ same residue
DCTN1 p.Ala142Ser 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

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-ala142pro (accessed [today's date]).

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