Is DHTKD1 p.Asp707Glu (c.2121C>A) pathogenic?

DHTKD1 p.Asp707Glu (c.2121C>A) is classified Benign/Likely benign in DHTKD1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.1791); Low-frequency (popmax 1.26%, afr); Associated with Charcot-Marie-Tooth disease axonal type 2Q.

What condition is associated with DHTKD1 p.Asp707Glu (c.2121C>A)?

DHTKD1 p.Asp707Glu (c.2121C>A) is associated with Charcot-Marie-Tooth disease axonal type 2Q, 2-aminoadipic 2-oxoadipic aciduria (ClinVar).

How common is DHTKD1 p.Asp707Glu (c.2121C>A) in the general population?

DHTKD1 p.Asp707Glu (c.2121C>A) is low-frequency (popmax 1.26%, afr) (gnomAD).

What do computational predictors say about DHTKD1 p.Asp707Glu (c.2121C>A)?

AlphaMissense predicts likely benign (score 0.1791) — an in-silico prediction, not a clinical call.

DHTKD1 p.Asp707Glu

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.2121C>A · rs35046964 · VCV786139

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1791 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.26%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease axonal type 2Q

Computational evidence

Protein change
AlphaMissense	0.1791	likely benign
REVEL	0.277	benign-leaning
SaProt	LLR 2.56	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.7	GERP -2.2
Regional constraint	o/e 1.05	unconstrained · MANE · 52 kb · p 0.072 · regional, not allelic
Overall
CADD	0.208	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 1.26% African / African-American · 947/75,038 alleles

Filtering AF 1.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.17%

Overall 0.135% 2,186/1,613,966 alleles · low-frequency

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	2.47%	40
African / African-Americangrpmax	1.26%	79
Remaining individualsnot grpmax-eligible	0.278%	359
Middle Eastern	0.247%	404
Admixed American	0.153%	652
European (non-Finnish)	0.0188%	5,315
South Asian	0.00439%	22,770

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp707Glu
Coding: c.2121C>A
MANE Select: NM_018706
dbSNP: rs35046964
Type: single nucleotide variant
Location: chr10:12107982 (GRCh38)
Gene constraint: LOEUF 0.864 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.19 · 8 PDB
Residue 707: a UniProt-annotated variant site (in aakad)

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 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.Arg455Ter 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-asp707glu (accessed [today's date]).

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