Is DYNC1H1 p.Ala3517Val (c.10550C>T) pathogenic?

DYNC1H1 p.Ala3517Val (c.10550C>T) is classified Uncertain significance in DYNC1H1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-14). AlphaMissense: likely pathogenic (0.7964); Very rare (popmax 0.00133%, afr); Associated with Charcot-Marie-Tooth disease axonal type 2O.

What condition is associated with DYNC1H1 p.Ala3517Val (c.10550C>T)?

DYNC1H1 p.Ala3517Val (c.10550C>T) is associated with Charcot-Marie-Tooth disease axonal type 2O, cortical dysplasia, complex, with other brain malformations 13 (ClinVar).

How common is DYNC1H1 p.Ala3517Val (c.10550C>T) in the general population?

DYNC1H1 p.Ala3517Val (c.10550C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about DYNC1H1 p.Ala3517Val (c.10550C>T)?

AlphaMissense predicts likely pathogenic (score 0.7964) — an in-silico prediction, not a clinical call.

DYNC1H1 p.Ala3517Val

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.10550C>T · rs1165122605 · VCV2585064

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7964 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

Charcot-Marie-Tooth disease axonal type 2O

Computational evidence

Protein change
AlphaMissense	0.7964	likely pathogenic
REVEL	0.431	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1, phastCons 1
Regional constraint	o/e 0.38	unconstrained · MANE · 7,350 bp · p 6.9e-63 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,056 alleles

Overall 0.000137% 2/1,461,828 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,056
European (non-Finnish)	8.47e-05%	1,180,044

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.Ala3517Val
Coding: c.10550C>T
MANE Select: NM_001376
dbSNP: rs1165122605
Type: single nucleotide variant
Location: chr14:102034112 (GRCh38)
Gene constraint: LOEUF 0.117 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 3517: a β-strand

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: cortical dysplasia, complex, with other brain malformations 13

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.Ala3517Thr Uncertain significance ★★ same residue
DYNC1H1 p.Ala3517= Likely benign ★ same residue
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

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-ala3517val (accessed [today's date]).

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