Is DYNC1H1 p.His306Arg (c.917A>G) pathogenic?

DYNC1H1 p.His306Arg (c.917A>G) is classified Pathogenic/Likely pathogenic in DYNC1H1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2023-10-05). AlphaMissense: likely benign (0.3257); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease axonal type 2O.

What condition is associated with DYNC1H1 p.His306Arg (c.917A>G)?

DYNC1H1 p.His306Arg (c.917A>G) is associated with Charcot-Marie-Tooth disease axonal type 2O, autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures, Charcot-Marie-Tooth disease (ClinVar).

How common is DYNC1H1 p.His306Arg (c.917A>G) in the general population?

DYNC1H1 p.His306Arg (c.917A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DYNC1H1 p.His306Arg (c.917A>G)?

AlphaMissense predicts likely benign (score 0.3257) — an in-silico prediction, not a clinical call.

DYNC1H1 p.His306Arg

Q: How is Autosomal dominant Charcot-Marie-Tooth disease type 2O inherited?

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

c.917A>G · rs387906738 · VCV30029

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.3257 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Charcot-Marie-Tooth disease axonal type 2O

Computational evidence

Protein change
AlphaMissense	0.3257	likely benign ⚠ discordant with ClinVar
REVEL	0.381	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.05	constrained · MANE · 44 bp · p 9e-06 · regional, not allelic
Overall
CADD	22.3	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.His306Arg
Coding: c.917A>G
MANE Select: NM_001376
dbSNP: rs387906738
Type: single nucleotide variant
Location: chr14:101980506 (GRCh38)
Gene constraint: LOEUF 0.117 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 306: the 'stem' region; a UniProt-annotated variant site (in cmt2o and smaled1); an α-helix

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

Disease context

Charcot-Marie-Tooth disease axonal type 2O — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures Charcot-Marie-Tooth disease

For Autosomal dominant Charcot-Marie-Tooth disease type 2O (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

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
DYNC1H1 p.Arg264Leu Pathogenic ★★ same condition
DYNC1H1 p.Arg264Pro 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-his306arg (accessed [today's date]).

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