Is DYNC1H1 p.Pro761= (c.2283A>G) pathogenic?

DYNC1H1 p.Pro761= (c.2283A>G) is classified Benign/Likely benign in DYNC1H1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-11-17). Rare (popmax 0.16%, eas); Associated with Charcot-Marie-Tooth disease axonal type 2O.

What condition is associated with DYNC1H1 p.Pro761= (c.2283A>G)?

DYNC1H1 p.Pro761= (c.2283A>G) is associated with Charcot-Marie-Tooth disease axonal type 2O (ClinVar).

How common is DYNC1H1 p.Pro761= (c.2283A>G) in the general population?

DYNC1H1 p.Pro761= (c.2283A>G) is rare (popmax 0.16%, eas) (gnomAD).

DYNC1H1 p.Pro761=

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.2283A>G · rs202008601 · VCV387585

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.16%, eas)

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 -20	GERP -4.5
Overall
CADD	0.547	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.16% East Asian · 72/44,880 alleles

Filtering AF 0.131% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.12%

Overall 0.00539% 87/1,614,194 alleles · rare exomes 74/1,461,894 · genomes 13/152,300 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.16%	623
Remaining individualsnot grpmax-eligible	0.0096%	10,418
African / African-American	0.00133%	75,044
South Asian	0.0011%	91,086
European (non-Finnish)	0.000593%	168,577

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.Pro761=
Coding: c.2283A>G
MANE Select: NM_001376
dbSNP: rs202008601
Type: single nucleotide variant
Location: chr14:101986508 (GRCh38)
Gene constraint: LOEUF 0.117 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 761: the 'stem' region; the 'interaction with dync1li2' 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.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-pro761 (accessed [today's date]).

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