Is DYNC1H1 p.Leu2976= (c.8928A>G) pathogenic?

DYNC1H1 p.Leu2976= (c.8928A>G) is classified Benign in DYNC1H1 (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-02-03). Common (popmax 23.6%, eas) — too common for a highly-penetrant pathogenic allele; Associated with autosomal dominant cerebellar ataxia.

DYNC1H1 p.Leu2976=

Q: What condition is associated with DYNC1H1 p.Leu2976= (c.8928A>G)?

DYNC1H1 p.Leu2976= (c.8928A>G) is associated with autosomal dominant cerebellar ataxia, autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures, Charcot-Marie-Tooth disease axonal type 2O (ClinVar).

Q: How common is DYNC1H1 p.Leu2976= (c.8928A>G) in the general population?

DYNC1H1 p.Leu2976= (c.8928A>G) is common (popmax 23.6%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.8928A>G · rs8010870 · VCV128944

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

gnomAD v4.1

Common

common (popmax 23.6%, eas) — too common for a highly-penetrant pathogenic allele

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 -7.4	GERP -5
Overall
CADD	0.399	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 23.6% East Asian · 10,590/44,868 alleles

Filtering AF 23.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 23.1%

Overall 11.9% 192,472/1,613,952 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	23.6%	4
African / African-American	22.6%	4
South Asian	17.3%	6
Ashkenazi Jewishnot grpmax-eligible	14.6%	7
Admixed American	14.6%	7
Remaining individualsnot grpmax-eligible	12.7%	8
Middle Eastern	12.4%	8
European (non-Finnish)	10.2%	10
Finnishnot grpmax-eligible	10%	10
Amishnot grpmax-eligible	4.5%	22

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.Leu2976=
Coding: c.8928A>G
MANE Select: NM_001376
dbSNP: rs8010870
Type: single nucleotide variant
Location: chr14:102027424 (GRCh38)
Gene constraint: LOEUF 0.117 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 2976: an α-helix; the 'aaa 4' 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: autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures Charcot-Marie-Tooth disease axonal type 2O cortical dysplasia, complex, with other brain malformations 13 Charcot-Marie-Tooth disease

Similar variants

DYNC1H1 p.Arg1567Gln Pathogenic/Likely pathogenic ★★ same condition
DYNC1H1 p.Arg1623Gln Pathogenic/Likely pathogenic ★★ same condition
DYNC1H1 p.Arg1623Trp 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.Arg2492Ter Likely pathogenic ★★ same condition
DYNC1H1 p.Arg251Ser Pathogenic/Likely 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-leu2976 (accessed [today's date]).

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