Is DHTKD1 p.Arg149Gln (c.446G>A) pathogenic?

DHTKD1 p.Arg149Gln (c.446G>A) is classified Uncertain significance in DHTKD1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-19). AlphaMissense: likely benign (0.1028); Very rare (popmax 0.00271%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DHTKD1 p.Arg149Gln (c.446G>A)?

DHTKD1 p.Arg149Gln (c.446G>A) is associated with Inborn genetic diseases, 2-aminoadipic 2-oxoadipic aciduria (ClinVar).

How common is DHTKD1 p.Arg149Gln (c.446G>A) in the general population?

DHTKD1 p.Arg149Gln (c.446G>A) is very rare (popmax 0.00271%, nfe) (gnomAD).

What do computational predictors say about DHTKD1 p.Arg149Gln (c.446G>A)?

AlphaMissense predicts likely benign (score 0.1028) — an in-silico prediction, not a clinical call.

DHTKD1 p.Arg149Gln

c.446G>A · rs773052090 · VCV1033499

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1028 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00271%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1028	likely benign
REVEL	0.28	benign-leaning
SaProt	LLR -10.24	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.5	GERP 2, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 52 kb · p 0.072 · regional, not allelic
Overall
CADD	21.8	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 0.00271% European (non-Finnish) · 32/1,180,026 alleles

Filtering AF 0.00196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00168%

Overall 0.00266% 43/1,613,976 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0125%	8,002
European (non-Finnish)grpmax	0.00271%	36,876
Remaining individualsnot grpmax-eligible	0.0016%	62,486
African / African-American	0.00134%	74,888
South Asian	0.0011%	91,090

Finnish 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.Arg149Gln
Coding: c.446G>A
MANE Select: NM_018706
dbSNP: rs773052090
Type: single nucleotide variant
Location: chr10:12084675 (GRCh38)
Gene constraint: LOEUF 0.864 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.19 · 8 PDB
Residue 149: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: 2-aminoadipic 2-oxoadipic aciduria

Similar variants

DHTKD1 p.Arg149= Likely benign ★★ same residue
DHTKD1 p.Arg149Trp 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-arg149gln (accessed [today's date]).

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