Is DYNC1H1 p.Arg598Pro (c.1793G>C) pathogenic?

DYNC1H1 p.Arg598Pro (c.1793G>C) is classified Likely pathogenic in DYNC1H1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-15). AlphaMissense: likely pathogenic (0.9994); Absent from gnomAD v4.1; Associated with autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures.

How common is DYNC1H1 p.Arg598Pro (c.1793G>C) in the general population?

DYNC1H1 p.Arg598Pro (c.1793G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DYNC1H1 p.Arg598Pro (c.1793G>C)?

AlphaMissense predicts likely pathogenic (score 0.9994) — an in-silico prediction, not a clinical call.

DYNC1H1 p.Arg598Pro

Q: What condition is associated with DYNC1H1 p.Arg598Pro (c.1793G>C)?

DYNC1H1 p.Arg598Pro (c.1793G>C) is associated with autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures (ClinVar).

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.1793G>C · rs879254085 · VCV2506366

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9994 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures

Computational evidence

Protein change
AlphaMissense	0.9994	likely pathogenic ✓ concordant with ClinVar · top 2% in DYNC1H1
REVEL	0.79	moderately pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.43	unconstrained · MANE · 3,602 bp · p 2.9e-46 · regional, not allelic
Overall
CADD	27.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

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.Arg598Pro
Coding: c.1793G>C
MANE Select: NM_001376
dbSNP: rs879254085
Type: single nucleotide variant
Location: chr14:101986018 (GRCh38)
Gene constraint: LOEUF 0.117 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 598: an α-helix; the 'stem' region; the 'interaction with dync1i2' region; a UniProt-annotated variant site (in cmt2o and smaled1; slight increased bicd2-binding)

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

Disease context

autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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.Arg598Cys Pathogenic/Likely pathogenic ★★ same residue
DYNC1H1 p.Arg598Leu Pathogenic ★★ same residue
DYNC1H1 p.Arg598His Likely pathogenic ★ same residue
DYNC1H1 p.Arg1962Cys Pathogenic ★★ same condition
DYNC1H1 p.Arg1962His Likely pathogenic ★★ same condition
DYNC1H1 p.Arg264Pro Likely pathogenic ★★ same condition
DYNC1H1 p.Glu580Ala Pathogenic/Likely pathogenic ★★ same condition
DYNC1H1 p.Gly1132Glu 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-arg598pro (accessed [today's date]).

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