Is DYNC1H1 p.Phe4147= (c.12441C>T) pathogenic?

DYNC1H1 p.Phe4147= (c.12441C>T) is classified Conflicting classifications of pathogenicity in DYNC1H1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-02). Ultra-rare (popmax 0.0329%, mid); Associated with Charcot-Marie-Tooth disease axonal type 2O.

What condition is associated with DYNC1H1 p.Phe4147= (c.12441C>T)?

DYNC1H1 p.Phe4147= (c.12441C>T) is associated with Charcot-Marie-Tooth disease axonal type 2O (ClinVar).

How common is DYNC1H1 p.Phe4147= (c.12441C>T) in the general population?

DYNC1H1 p.Phe4147= (c.12441C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

DYNC1H1 p.Phe4147=

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.12441C>T · rs146075696 · VCV539808

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Conditions

Charcot-Marie-Tooth disease axonal type 2O

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 -9.2	GERP -4.5
Overall
CADD	3.172	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.00285% 46/1,614,014 alleles · ultra-rare exomes 44/1,461,862 · genomes 2/152,152 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
Remaining individualsnot grpmax-eligible	0.0112%	8,927
African / African-American	0.00401%	24,969
European (non-Finnish)	0.00254%	39,335
East Asian	0.00223%	44,888
South Asian	0.0022%	45,543
Admixed American	0.00167%	59,986

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.Phe4147=
Coding: c.12441C>T
MANE Select: NM_001376
dbSNP: rs146075696
Type: single nucleotide variant
Location: chr14:102042676 (GRCh38)
Gene constraint: LOEUF 0.117 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 4147: the 'aaa 6' region; 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

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.Phe4147Leu 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-phe4147 (accessed [today's date]).

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