Is DHTKD1 p.Leu488Phe (c.1464G>C) pathogenic?

DHTKD1 p.Leu488Phe (c.1464G>C) is classified Uncertain significance in DHTKD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-22). AlphaMissense: ambiguous (0.5213); Very rare (popmax 6.84e-05%); Associated with Inborn genetic diseases.

What condition is associated with DHTKD1 p.Leu488Phe (c.1464G>C)?

DHTKD1 p.Leu488Phe (c.1464G>C) is associated with Inborn genetic diseases (ClinVar).

How common is DHTKD1 p.Leu488Phe (c.1464G>C) in the general population?

DHTKD1 p.Leu488Phe (c.1464G>C) is very rare (popmax 6.84e-05%) (gnomAD).

What do computational predictors say about DHTKD1 p.Leu488Phe (c.1464G>C)?

AlphaMissense predicts ambiguous (score 0.5213) — an in-silico prediction, not a clinical call.

DHTKD1 p.Leu488Phe

c.1464G>C · VCV3839786

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5213 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5213	ambiguous
REVEL	0.789	moderately pathogenic-leaning
SaProt	LLR -12.34	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -3.9, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 52 kb · p 0.072 · regional, not allelic
Overall
CADD	19.99	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 6.84e-05%

Overall 6.84e-05% 1/1,461,886 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.Leu488Phe
Coding: c.1464G>C
MANE Select: NM_018706
Type: single nucleotide variant
Location: chr10:12097789 (GRCh38)
Gene constraint: LOEUF 0.864 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.19 · 8 PDB
Residue 488: 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.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
DHTKD1 p.Ala915Pro 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-leu488phe (accessed [today's date]).

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