Is DHTKD1 p.Asp312Asn (c.934G>A) pathogenic?

DHTKD1 p.Asp312Asn (c.934G>A) is classified Uncertain significance in DHTKD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-07). AlphaMissense: ambiguous (0.487); Ultra-rare (popmax 0.0329%, mid); Associated with 2-aminoadipic 2-oxoadipic aciduria.

What condition is associated with DHTKD1 p.Asp312Asn (c.934G>A)?

DHTKD1 p.Asp312Asn (c.934G>A) is associated with 2-aminoadipic 2-oxoadipic aciduria (ClinVar).

How common is DHTKD1 p.Asp312Asn (c.934G>A) in the general population?

DHTKD1 p.Asp312Asn (c.934G>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

How is 2-aminoadipic 2-oxoadipic aciduria inherited?

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

What do computational predictors say about DHTKD1 p.Asp312Asn (c.934G>A)?

AlphaMissense predicts ambiguous (score 0.487) — an in-silico prediction, not a clinical call.

DHTKD1 p.Asp312Asn

c.934G>A · rs775089419 · VCV2158718

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.487 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

2-aminoadipic 2-oxoadipic aciduria

Computational evidence

Protein change
AlphaMissense	0.487	ambiguous
REVEL	0.209	benign-leaning
SaProt	LLR -9.98	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 0.92, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 52 kb · p 0.072 · regional, not allelic
Overall
CADD	23.4	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 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.018%

Overall 0.00211% 34/1,614,016 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
South Asian	0.0296%	3,373
East Asian	0.00223%	44,900
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.000254%	393,343

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.Asp312Asn
Coding: c.934G>A
MANE Select: NM_018706
dbSNP: rs775089419
Type: single nucleotide variant
Location: chr10:12089202 (GRCh38)
Gene constraint: LOEUF 0.864 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.19 · 8 PDB
Residue 312: the 'disordered' region; an α-helix

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-asp312asn (accessed [today's date]).

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