Is DYNC1H1 p.Leu4025= (c.12075C>T) pathogenic?

DYNC1H1 p.Leu4025= (c.12075C>T) is classified Likely benign in DYNC1H1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-10-13). Ultra-rare (popmax 0.0107%, afr); Associated with autosomal dominant cerebellar ataxia.

What condition is associated with DYNC1H1 p.Leu4025= (c.12075C>T)?

DYNC1H1 p.Leu4025= (c.12075C>T) is associated with autosomal dominant cerebellar ataxia, Charcot-Marie-Tooth disease axonal type 2O, Charcot-Marie-Tooth disease (ClinVar).

How common is DYNC1H1 p.Leu4025= (c.12075C>T) in the general population?

DYNC1H1 p.Leu4025= (c.12075C>T) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

DYNC1H1 p.Leu4025=

c.12075C>T · rs373636519 · VCV516470

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Conditions

autosomal dominant cerebellar ataxia

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 -11	GERP -4.7
Overall
CADD	0.972	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0107% African / African-American · 8/74,932 alleles

Filtering AF 0.00842% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00787%

Overall 0.00799% 129/1,614,050 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,367
European (non-Finnish)	0.00991%	10,086
Admixed American	0.00333%	30,006
Finnishnot grpmax-eligible	0.00156%	63,994
South Asian	0.0011%	91,084

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.Leu4025=
Coding: c.12075C>T
MANE Select: NM_001376
dbSNP: rs373636519
Type: single nucleotide variant
Location: chr14:102041707 (GRCh38)
Gene constraint: LOEUF 0.117 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 4025: the 'aaa 6' region

Full DYNC1H1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal dominant cerebellar ataxia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charcot-Marie-Tooth disease axonal type 2O Charcot-Marie-Tooth disease

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-leu4025 (accessed [today's date]).

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