Is DYNC1H1 p.Arg2235Cys (c.6703C>T) pathogenic?

DYNC1H1 p.Arg2235Cys (c.6703C>T) is classified Uncertain significance in DYNC1H1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-06-06). AlphaMissense: likely benign (0.3021); Very rare (popmax 0.000254%, nfe); Associated with Charcot-Marie-Tooth disease axonal type 2O.

What condition is associated with DYNC1H1 p.Arg2235Cys (c.6703C>T)?

DYNC1H1 p.Arg2235Cys (c.6703C>T) is associated with Charcot-Marie-Tooth disease axonal type 2O, cortical dysplasia, complex, with other brain malformations 13 (ClinVar).

How common is DYNC1H1 p.Arg2235Cys (c.6703C>T) in the general population?

DYNC1H1 p.Arg2235Cys (c.6703C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about DYNC1H1 p.Arg2235Cys (c.6703C>T)?

AlphaMissense predicts likely benign (score 0.3021) — an in-silico prediction, not a clinical call.

DYNC1H1 p.Arg2235Cys

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.6703C>T · rs2048263659 · VCV937426

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.3021 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

Charcot-Marie-Tooth disease axonal type 2O

Computational evidence

Protein change
AlphaMissense	0.3021	likely benign
REVEL	0.474	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.30	constrained · MANE · 3,245 bp · p 4.2e-21 · regional, not allelic
Overall
CADD	26.2	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

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,008 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,884 alleles · very rare

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: DYNC1H1
Protein: p.Arg2235Cys
Coding: c.6703C>T
MANE Select: NM_001376
dbSNP: rs2048263659
Type: single nucleotide variant
Location: chr14:102011959 (GRCh38)
Gene constraint: LOEUF 0.117 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 2235: an α-helix; the 'aaa 2' region

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: cortical dysplasia, complex, with other brain malformations 13

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.Arg2235His Conflicting classifications of pathogenicity ★ same residue
DYNC1H1 p.Arg2235Ser Uncertain significance ★ same residue
DYNC1H1 p.Arg2235Leu Uncertain significance ★ same residue
DYNC1H1 p.Arg1567Gln Pathogenic/Likely pathogenic ★★ same condition
DYNC1H1 p.Arg1623Gln Pathogenic/Likely pathogenic ★★ same condition
DYNC1H1 p.Arg1623Trp Pathogenic ★★ same condition
DYNC1H1 p.Arg1962Cys Pathogenic ★★ same condition
DYNC1H1 p.Arg1962His 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-arg2235cys (accessed [today's date]).

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