Is DYNC1H1 p.Ile520= (c.1560T>C) pathogenic?

DYNC1H1 p.Ile520= (c.1560T>C) is classified Conflicting classifications of pathogenicity in DYNC1H1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-01-20). Very rare (popmax 0.000508%, nfe); Associated with Charcot-Marie-Tooth disease axonal type 2O.

What condition is associated with DYNC1H1 p.Ile520= (c.1560T>C)?

DYNC1H1 p.Ile520= (c.1560T>C) is associated with Charcot-Marie-Tooth disease axonal type 2O, autosomal dominant cerebellar ataxia (ClinVar).

How common is DYNC1H1 p.Ile520= (c.1560T>C) in the general population?

DYNC1H1 p.Ile520= (c.1560T>C) is very rare (popmax 0.000508%, nfe) (gnomAD).

DYNC1H1 p.Ile520=

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.1560T>C · rs761916499 · VCV389700

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000508%, 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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8	GERP -4.6
Overall
CADD	0.706	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000508% European (non-Finnish) · 6/1,180,032 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.00496% 80/1,613,980 alleles · very rare exomes 67/1,461,894 · genomes 13/152,086 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.106%	942
Remaining individualsnot grpmax-eligible	0.0096%	10,413
European (non-Finnish)grpmax	0.000508%	196,672

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ile520=
Coding: c.1560T>C
MANE Select: NM_001376
dbSNP: rs761916499
Type: single nucleotide variant
Location: chr14:101985785 (GRCh38)
Gene constraint: LOEUF 0.117 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 520: an α-helix; the 'stem' region; the 'interaction with dync1i2' 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: autosomal dominant cerebellar ataxia

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-ile520 (accessed [today's date]).

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