Is DYNC1H1 p.Ser4010Pro (c.12028T>C) pathogenic?

DYNC1H1 p.Ser4010Pro (c.12028T>C) is classified Uncertain significance in DYNC1H1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-13). AlphaMissense: likely pathogenic (0.8831); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease axonal type 2O.

What condition is associated with DYNC1H1 p.Ser4010Pro (c.12028T>C)?

DYNC1H1 p.Ser4010Pro (c.12028T>C) is associated with Charcot-Marie-Tooth disease axonal type 2O (ClinVar).

How common is DYNC1H1 p.Ser4010Pro (c.12028T>C) in the general population?

DYNC1H1 p.Ser4010Pro (c.12028T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DYNC1H1 p.Ser4010Pro (c.12028T>C)?

AlphaMissense predicts likely pathogenic (score 0.8831) — an in-silico prediction, not a clinical call.

DYNC1H1 p.Ser4010Pro

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.12028T>C · rs2503855782 · VCV2864812

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8831 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Charcot-Marie-Tooth disease axonal type 2O

Computational evidence

Protein change
AlphaMissense	0.8831	likely pathogenic
REVEL	0.203	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 2.2, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 1,969 bp · p 0.00098 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DYNC1H1
Protein: p.Ser4010Pro
Coding: c.12028T>C
MANE Select: NM_001376
dbSNP: rs2503855782
Type: single nucleotide variant
Location: chr14:102041660 (GRCh38)
Gene constraint: LOEUF 0.117 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 4010: the 'aaa 6' region; an α-helix

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

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.Ser4010Leu Uncertain significance ★ ⚠ 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-ser4010pro (accessed [today's date]).

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