Is DYNC1H1 p.Arg3474Trp (c.10420C>T) pathogenic?

DYNC1H1 p.Arg3474Trp (c.10420C>T) is classified Pathogenic/Likely pathogenic in DYNC1H1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-01-10). AlphaMissense: likely pathogenic (0.9923); Absent from gnomAD v4.1; Associated with autosomal dominant childhood-onset proximal spinal muscular atrophy.

What condition is associated with DYNC1H1 p.Arg3474Trp (c.10420C>T)?

DYNC1H1 p.Arg3474Trp (c.10420C>T) is associated with autosomal dominant childhood-onset proximal spinal muscular atrophy, Charcot-Marie-Tooth disease axonal type 2O, lissencephaly spectrum disorders (ClinVar).

How common is DYNC1H1 p.Arg3474Trp (c.10420C>T) in the general population?

DYNC1H1 p.Arg3474Trp (c.10420C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DYNC1H1 p.Arg3474Trp (c.10420C>T)?

AlphaMissense predicts likely pathogenic (score 0.9923) — an in-silico prediction, not a clinical call.

DYNC1H1 p.Arg3474Trp

Q: How is Autosomal dominant childhood-onset proximal spinal muscular atrophy inherited?

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

c.10420C>T · rs757725348 · VCV246393

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9923 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

autosomal dominant childhood-onset proximal spinal muscular atrophy

Computational evidence

Protein change
AlphaMissense	0.9923	likely pathogenic ✓ concordant with ClinVar
REVEL	0.739	pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP 1.2, phastCons 1
Regional constraint	o/e 0.38	unconstrained · MANE · 7,350 bp · p 6.9e-63 · regional, not allelic
Overall
CADD	23.8	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

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: DYNC1H1
Protein: p.Arg3474Trp
Coding: c.10420C>T
MANE Select: NM_001376
dbSNP: rs757725348
Type: single nucleotide variant
Location: chr14:102033982 (GRCh38)
Gene constraint: LOEUF 0.117 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 3474: the 'stalk' region; an α-helix

Full DYNC1H1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal dominant childhood-onset proximal spinal muscular atrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charcot-Marie-Tooth disease axonal type 2O lissencephaly spectrum disorders

For Autosomal dominant childhood-onset proximal spinal muscular atrophy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Antenatal, Childhood, Infancy, Neonatal
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

DYNC1H1 p.Arg3474Gln Uncertain significance ★ same residue
DYNC1H1 p.Arg3474= Likely benign ★ same residue
DYNC1H1 p.Arg1567Gln Pathogenic/Likely pathogenic ★★ same condition
DYNC1H1 p.Arg1623Gln Pathogenic/Likely pathogenic ★★ same condition
DYNC1H1 p.Arg1962Cys Pathogenic ★★ same condition
DYNC1H1 p.Arg1962His Likely pathogenic ★★ same condition
DYNC1H1 p.Arg2332Cys Pathogenic/Likely pathogenic ★★ same condition
DYNC1H1 p.Arg251Ser Pathogenic/Likely pathogenic ★★ 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/dync1h1-p-arg3474trp (accessed [today's date]).

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