Is DHTKD1 p.Ala496= (c.1488C>G) pathogenic?

DHTKD1 p.Ala496= (c.1488C>G) is classified Likely benign in DHTKD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-11). Ultra-rare (popmax 0.0133%, amr); Associated with 2-aminoadipic 2-oxoadipic aciduria.

What condition is associated with DHTKD1 p.Ala496= (c.1488C>G)?

DHTKD1 p.Ala496= (c.1488C>G) is associated with 2-aminoadipic 2-oxoadipic aciduria (ClinVar).

How common is DHTKD1 p.Ala496= (c.1488C>G) in the general population?

DHTKD1 p.Ala496= (c.1488C>G) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

How is 2-aminoadipic 2-oxoadipic aciduria inherited?

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

DHTKD1 p.Ala496=

c.1488C>G · VCV4751817

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Conditions

2-aminoadipic 2-oxoadipic aciduria

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.337	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.43	GERP -3.6, phastCons 0.029
Overall
CADD	4.25	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% Admixed American · 8/60,016 alleles

Filtering AF 0.00661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.000616% 9/1,461,892 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,502
Remaining individualsnot grpmax-eligible	0.0016%	62,510

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.Ala496=
Coding: c.1488C>G
MANE Select: NM_018706
Type: single nucleotide variant
Location: chr10:12097813 (GRCh38)
Gene constraint: LOEUF 0.864 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.19 · 8 PDB
Residue 496: a UniProt-annotated variant site (in aakad); a turn

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

Disease context

2-aminoadipic 2-oxoadipic aciduria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For 2-aminoadipic 2-oxoadipic aciduria (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

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-ala496 (accessed [today's date]).

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