Is DHTKD1 p.Ile680Met (c.2040C>G) pathogenic?

DHTKD1 p.Ile680Met (c.2040C>G) is classified Uncertain significance in DHTKD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-22). AlphaMissense: likely benign (0.2363); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with DHTKD1 p.Ile680Met (c.2040C>G)?

DHTKD1 p.Ile680Met (c.2040C>G) is associated with Inborn genetic diseases (ClinVar).

How common is DHTKD1 p.Ile680Met (c.2040C>G) in the general population?

DHTKD1 p.Ile680Met (c.2040C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DHTKD1 p.Ile680Met (c.2040C>G)?

AlphaMissense predicts likely benign (score 0.2363) — an in-silico prediction, not a clinical call.

DHTKD1 p.Ile680Met

c.2040C>G · rs2491503986 · VCV3082139

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2363 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2363	likely benign
REVEL	0.851	moderately pathogenic-leaning
SaProt	LLR -9.24	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 1.1	GERP 1.1, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 52 kb · p 0.072 · regional, not allelic
Overall
CADD	23.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DHTKD1
Protein: p.Ile680Met
Coding: c.2040C>G
MANE Select: NM_018706
dbSNP: rs2491503986
Type: single nucleotide variant
Location: chr10:12106389 (GRCh38)
Gene constraint: LOEUF 0.864 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.19 · 8 PDB
Residue 680: 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

Similar variants

DHTKD1 p.Ile680Thr Uncertain significance ★ ⚠ same residue
DHTKD1 p.Trp861Ter Pathogenic ★★ same condition
DHTKD1 c.1159+5G>A Uncertain significance ★★ same condition
DHTKD1 p.Ala113Pro Uncertain significance ★★ ⚠ same condition
DHTKD1 p.Ala275Val Uncertain significance ★★ ⚠ same condition
DHTKD1 p.Ala297Val Uncertain significance ★★ ⚠ same condition
DHTKD1 p.Ala723Val Uncertain significance ★★ ⚠ same condition
DHTKD1 p.Ala81Thr Uncertain significance ★★ ⚠ 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-ile680met (accessed [today's date]).

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