Is DYNC1H1 p.Val765Ala (c.2294T>C) pathogenic?

DYNC1H1 p.Val765Ala (c.2294T>C) is classified Uncertain significance in DYNC1H1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-07). AlphaMissense: likely pathogenic (0.9256); Very rare (popmax 0.000169%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DYNC1H1 p.Val765Ala (c.2294T>C)?

DYNC1H1 p.Val765Ala (c.2294T>C) is associated with Inborn genetic diseases, Charcot-Marie-Tooth disease axonal type 2O (ClinVar).

How common is DYNC1H1 p.Val765Ala (c.2294T>C) in the general population?

DYNC1H1 p.Val765Ala (c.2294T>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about DYNC1H1 p.Val765Ala (c.2294T>C)?

AlphaMissense predicts likely pathogenic (score 0.9256) — an in-silico prediction, not a clinical call.

DYNC1H1 p.Val765Ala

c.2294T>C · rs1001125376 · VCV942037

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9256 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9256	likely pathogenic
REVEL	0.154	moderately benign-leaning
⇒ AlphaMissense calls this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.43	unconstrained · MANE · 3,602 bp · p 2.9e-46 · regional, not allelic
Overall
CADD	23.4	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 0.000169% European (non-Finnish) · 2/1,180,034 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.00131% 2/152,146 alleles · very rare

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.Val765Ala
Coding: c.2294T>C
MANE Select: NM_001376
dbSNP: rs1001125376
Type: single nucleotide variant
Location: chr14:101986519 (GRCh38)
Gene constraint: LOEUF 0.117 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 765: an α-helix; the 'stem' region; the 'interaction with dync1li2' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

DYNC1H1 p.Val765= Likely benign ★ same residue
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

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-val765ala (accessed [today's date]).

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