Is DYNC1H1 p.Arg1253= (c.3759C>T) pathogenic?

DYNC1H1 p.Arg1253= (c.3759C>T) is classified Likely benign in DYNC1H1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-23). Ultra-rare (popmax 0.01%, amr); Associated with Charcot-Marie-Tooth disease axonal type 2O.

What condition is associated with DYNC1H1 p.Arg1253= (c.3759C>T)?

DYNC1H1 p.Arg1253= (c.3759C>T) is associated with Charcot-Marie-Tooth disease axonal type 2O (ClinVar).

How common is DYNC1H1 p.Arg1253= (c.3759C>T) in the general population?

DYNC1H1 p.Arg1253= (c.3759C>T) is ultra-rare (popmax 0.01%, amr) (gnomAD).

DYNC1H1 p.Arg1253=

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.3759C>T · rs374582145 · VCV1217522

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Conditions

Charcot-Marie-Tooth disease axonal type 2O

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.47	GERP -1.9, phastCons 0.027
Overall
CADD	9.553	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/59,992 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00112% 18/1,613,888 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,999
African / African-American	0.00668%	14,975
Remaining individualsnot grpmax-eligible	0.0032%	31,242
South Asian	0.0011%	91,056
European (non-Finnish)	0.000339%	295,000

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.Arg1253=
Coding: c.3759C>T
MANE Select: NM_001376
dbSNP: rs374582145
Type: single nucleotide variant
Location: chr14:101997229 (GRCh38)
Gene constraint: LOEUF 0.117 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 1253: an α-helix; the 'stem' 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

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.Arg1253His Uncertain significance ★ 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
DYNC1H1 p.Arg264Leu 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-arg1253 (accessed [today's date]).

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