Is DHTKD1 p.Arg455Ter (c.1363C>T) pathogenic?

DHTKD1 p.Arg455Ter (c.1363C>T) is classified Pathogenic/Likely pathogenic in DHTKD1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-23). Very rare (popmax 0.00807%, nfe); Associated with Charcot-Marie-Tooth disease axonal type 2Q.

What condition is associated with DHTKD1 p.Arg455Ter (c.1363C>T)?

DHTKD1 p.Arg455Ter (c.1363C>T) is associated with Charcot-Marie-Tooth disease axonal type 2Q, 2-aminoadipic 2-oxoadipic aciduria (ClinVar).

How common is DHTKD1 p.Arg455Ter (c.1363C>T) in the general population?

DHTKD1 p.Arg455Ter (c.1363C>T) is very rare (popmax 0.00807%, nfe) (gnomAD).

DHTKD1 p.Arg455Ter

Q: How is Autosomal dominant Charcot-Marie-Tooth disease type 2Q inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1363C>T · rs201369986 · VCV1033496

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00807%, nfe)

Conditions

Charcot-Marie-Tooth disease axonal type 2Q

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 17
REVEL	0.143	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 0.94, phastCons 1
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00807% European (non-Finnish) · 95/1,177,016 alleles

Filtering AF 0.00674% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00626%

Overall 0.00609% 98/1,607,956 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00807%	12,390
South Asian	0.00332%	30,081

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: DHTKD1
Protein: p.Arg455Ter
Coding: c.1363C>T
MANE Select: NM_018706
dbSNP: rs201369986
Type: single nucleotide variant
Location: chr10:12097688 (GRCh38)
Gene constraint: LOEUF 0.864 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.19 · 8 PDB
Residue 455: a UniProt-annotated variant site (in aakad); a UniProt-annotated variant site (in aakad; uncertain significance)

Full DHTKD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease axonal type 2Q — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: 2-aminoadipic 2-oxoadipic aciduria

For Autosomal dominant Charcot-Marie-Tooth disease type 2Q (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult

Similar variants

DHTKD1 p.Arg455Gln Uncertain significance ★★ ⚠ same residue
DHTKD1 c.1671+1G>A Likely pathogenic ★★ same condition
DHTKD1 c.1897-1G>A Pathogenic/Likely pathogenic ★★ same condition
DHTKD1 c.2320-2A>T Likely pathogenic ★★ same condition
DHTKD1 c.2572+1G>A Likely pathogenic ★★ same condition
DHTKD1 p.Arg163Ter Pathogenic ★★ same condition
DHTKD1 p.Arg410Ter Pathogenic/Likely pathogenic ★★ same condition
DHTKD1 p.Arg712Ter 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/dhtkd1-p-arg455ter (accessed [today's date]).

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