Is DYNC1H1 p.Arg264Pro (c.791G>C) pathogenic?

DYNC1H1 p.Arg264Pro (c.791G>C) is classified Likely pathogenic in DYNC1H1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-09-27). AlphaMissense: likely pathogenic (0.9993); Absent from gnomAD v4.1; Associated with autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures.

How common is DYNC1H1 p.Arg264Pro (c.791G>C) in the general population?

DYNC1H1 p.Arg264Pro (c.791G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DYNC1H1 p.Arg264Pro (c.791G>C)?

AlphaMissense predicts likely pathogenic (score 0.9993) — an in-silico prediction, not a clinical call.

DYNC1H1 p.Arg264Pro

Q: What condition is associated with DYNC1H1 p.Arg264Pro (c.791G>C)?

DYNC1H1 p.Arg264Pro (c.791G>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.791G>C · rs713993043 · VCV1685305

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9993 · 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	0.9993	likely pathogenic ✓ concordant with ClinVar · top 2% in DYNC1H1
REVEL	0.647	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 2.3, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 16 kb · p 5.6e-17 · regional, not allelic
Overall
CADD	27.5	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.Arg264Pro
Coding: c.791G>C
MANE Select: NM_001376
dbSNP: rs713993043
Type: single nucleotide variant
Location: chr14:101980380 (GRCh38)
Gene constraint: LOEUF 0.117 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 264: the 'stem' region; a UniProt-annotated variant site (in 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.Arg264Leu Pathogenic ★★ same residue
DYNC1H1 p.Arg264Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
DYNC1H1 p.Arg264Ter Uncertain significance ★ same residue
DYNC1H1 p.Arg1962Cys Pathogenic ★★ same condition
DYNC1H1 p.Arg1962His Likely pathogenic ★★ same condition
DYNC1H1 p.Arg598Cys Pathogenic/Likely pathogenic ★★ same condition
DYNC1H1 p.Arg598Leu Pathogenic ★★ same condition
DYNC1H1 p.Glu580Ala 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-arg264pro (accessed [today's date]).

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