Is DYNC1H1 p.Ser2140= (c.6420C>T) pathogenic?

DYNC1H1 p.Ser2140= (c.6420C>T) is classified Likely benign in DYNC1H1 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-06-27). Very rare (popmax 0.0022%, nfe); Associated with Charcot-Marie-Tooth disease axonal type 2O.

What condition is associated with DYNC1H1 p.Ser2140= (c.6420C>T)?

DYNC1H1 p.Ser2140= (c.6420C>T) is associated with Charcot-Marie-Tooth disease axonal type 2O (ClinVar).

How common is DYNC1H1 p.Ser2140= (c.6420C>T) in the general population?

DYNC1H1 p.Ser2140= (c.6420C>T) is very rare (popmax 0.0022%, nfe) (gnomAD).

DYNC1H1 p.Ser2140=

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.6420C>T · rs759977828 · VCV2976821

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0022%, nfe)

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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -5.2	GERP -4.6
Overall
CADD	9.849	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% European (non-Finnish) · 26/1,179,916 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00174% 28/1,612,742 alleles · very rare exomes 27/1,460,498 · genomes 1/152,244 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0022%	45,381
Remaining individualsnot grpmax-eligible	0.0016%	62,348
South Asian	0.0011%	91,028

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.Ser2140=
Coding: c.6420C>T
MANE Select: NM_001376
dbSNP: rs759977828
Type: single nucleotide variant
Location: chr14:102010754 (GRCh38)
Gene constraint: LOEUF 0.117 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 2140: 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

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.Arg292Trp 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-ser2140 (accessed [today's date]).

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