Is DHTKD1 p.Pro773= (c.2319G>A) pathogenic?

DHTKD1 p.Pro773= (c.2319G>A) is classified Uncertain significance in DHTKD1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-10). Ultra-rare (popmax 0.0996%, afr); Associated with 2-aminoadipic 2-oxoadipic aciduria.

What condition is associated with DHTKD1 p.Pro773= (c.2319G>A)?

DHTKD1 p.Pro773= (c.2319G>A) is associated with 2-aminoadipic 2-oxoadipic aciduria (ClinVar).

How common is DHTKD1 p.Pro773= (c.2319G>A) in the general population?

DHTKD1 p.Pro773= (c.2319G>A) is ultra-rare (popmax 0.0996%, afr) (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.Pro773=

c.2319G>A · rs145738102 · VCV1009821

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0996%, afr)

Conditions

2-aminoadipic 2-oxoadipic aciduria

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.67	donor loss · deltas
Pangolin	Δ0.52	loss · gain 0.45 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -1.6	GERP -3.2
Overall
CADD	8.772	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0996% African / African-American · 74/74,334 alleles

Filtering AF 0.0813% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0746%

Overall 0.00568% 91/1,601,506 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0996%	1,005
Admixed American	0.0121%	8,269
Remaining individualsnot grpmax-eligible	0.00323%	30,976
Finnishnot grpmax-eligible	0.00157%	63,840
European (non-Finnish)	0.000596%	167,761

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.Pro773=
Coding: c.2319G>A
MANE Select: NM_018706
dbSNP: rs145738102
Type: single nucleotide variant
Location: chr10:12113064 (GRCh38)
Gene constraint: LOEUF 0.864 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.19 · 8 PDB
Residue 773: a UniProt-annotated variant site (in aakad); a UniProt-annotated variant site (in aakad; uncertain significance; thermally more labile than wild-type protein)

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 p.Pro773Leu Uncertain significance ★★ ⚠ same residue
DHTKD1 p.Pro773Gln 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

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-pro773 (accessed [today's date]).

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