Is DHTKD1 p.Arg420Pro (c.1259G>C) pathogenic?

DHTKD1 p.Arg420Pro (c.1259G>C) is classified Uncertain significance in DHTKD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-28). AlphaMissense: likely pathogenic (0.9441); Very rare (popmax 0.00381%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DHTKD1 p.Arg420Pro (c.1259G>C)?

DHTKD1 p.Arg420Pro (c.1259G>C) is associated with Inborn genetic diseases (ClinVar).

How common is DHTKD1 p.Arg420Pro (c.1259G>C) in the general population?

DHTKD1 p.Arg420Pro (c.1259G>C) is very rare (popmax 0.00381%, nfe) (gnomAD).

What do computational predictors say about DHTKD1 p.Arg420Pro (c.1259G>C)?

AlphaMissense predicts likely pathogenic (score 0.9441) — an in-silico prediction, not a clinical call.

DHTKD1 p.Arg420Pro

c.1259G>C · VCV4617305

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9441 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00381%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9441	likely pathogenic
REVEL	0.723	pathogenic-leaning
SaProt	LLR -12.52	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.5, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 52 kb · p 0.072 · regional, not allelic
Overall
CADD	28.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00381% European (non-Finnish) · 45/1,180,032 alleles

Filtering AF 0.00291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00285% 46/1,614,026 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00381%	26,223
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Arg420Pro
Coding: c.1259G>C
MANE Select: NM_018706
Type: single nucleotide variant
Location: chr10:12094172 (GRCh38)
Gene constraint: LOEUF 0.864 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.19 · 8 PDB

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.Arg420Cys Uncertain significance ★★ ⚠ same residue
DHTKD1 p.Arg420His Uncertain significance ★★ ⚠ same residue
DHTKD1 p.Arg420Leu 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

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-arg420pro (accessed [today's date]).

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