Is DHTKD1 p.Ser581Cys (c.1742C>G) pathogenic?

DHTKD1 p.Ser581Cys (c.1742C>G) is classified Uncertain significance in DHTKD1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-07). AlphaMissense: likely benign (0.1364); Very rare (popmax 0.00044%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DHTKD1 p.Ser581Cys (c.1742C>G)?

DHTKD1 p.Ser581Cys (c.1742C>G) is associated with Inborn genetic diseases, 2-aminoadipic 2-oxoadipic aciduria (ClinVar).

How common is DHTKD1 p.Ser581Cys (c.1742C>G) in the general population?

DHTKD1 p.Ser581Cys (c.1742C>G) is very rare (popmax 0.00044%, nfe) (gnomAD).

What do computational predictors say about DHTKD1 p.Ser581Cys (c.1742C>G)?

AlphaMissense predicts likely benign (score 0.1364) — an in-silico prediction, not a clinical call.

DHTKD1 p.Ser581Cys

c.1742C>G · rs1348311643 · VCV1421491

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1364 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00044%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1364	likely benign
REVEL	0.842	moderately pathogenic-leaning
SaProt	LLR -9.20	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 52 kb · p 0.072 · regional, not allelic
Overall
CADD	25.8	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 0.00044% European (non-Finnish) · 4/908,210 alleles

Filtering AF 0.000103% ClinGen BA1/BS1 input FAF95, joint · FAF99 7e-05%

Overall 0.000327% 4/1,222,086 alleles · very rare

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.Ser581Cys
Coding: c.1742C>G
MANE Select: NM_018706
dbSNP: rs1348311643
Type: single nucleotide variant
Location: chr10:12100248 (GRCh38)
Gene constraint: LOEUF 0.864 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.19 · 8 PDB
Residue 581: a UniProt-annotated variant site (in aakad); 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.Ser581Pro 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
DHTKD1 p.Arg455Ter 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-ser581cys (accessed [today's date]).

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