Is DYNC1H1 p.Phe3957Ser (c.11870T>C) pathogenic?

DYNC1H1 p.Phe3957Ser (c.11870T>C) is classified Uncertain significance in DYNC1H1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-01). AlphaMissense: likely pathogenic (0.9275); Very rare (popmax 0.00223%, eas); Associated with Charcot-Marie-Tooth disease axonal type 2O.

What condition is associated with DYNC1H1 p.Phe3957Ser (c.11870T>C)?

DYNC1H1 p.Phe3957Ser (c.11870T>C) is associated with Charcot-Marie-Tooth disease axonal type 2O, intellectual disability (ClinVar).

How common is DYNC1H1 p.Phe3957Ser (c.11870T>C) in the general population?

DYNC1H1 p.Phe3957Ser (c.11870T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about DYNC1H1 p.Phe3957Ser (c.11870T>C)?

AlphaMissense predicts likely pathogenic (score 0.9275) — an in-silico prediction, not a clinical call.

DYNC1H1 p.Phe3957Ser

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.11870T>C · rs2048637475 · VCV981306

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9275 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Charcot-Marie-Tooth disease axonal type 2O

Computational evidence

Protein change
AlphaMissense	0.9275	likely pathogenic
REVEL	0.515	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 2.4, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 1,969 bp · p 0.00098 · regional, not allelic
Overall
CADD	25.3	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

Grpmax group 0.00223% East Asian · 1/44,890 alleles

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

Overall 0.000248% 4/1,614,176 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,890
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	0.000169%	590,012

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.Phe3957Ser
Coding: c.11870T>C
MANE Select: NM_001376
dbSNP: rs2048637475
Type: single nucleotide variant
Location: chr14:102040602 (GRCh38)
Gene constraint: LOEUF 0.117 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 3957: 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

Also linked: intellectual disability

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.Phe3957Cys 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.Arg2332His Pathogenic/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-phe3957ser (accessed [today's date]).

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