Is DTX4 p.His490Pro (c.1469A>C) pathogenic?

DTX4 p.His490Pro (c.1469A>C) is classified Uncertain significance in DTX4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-10). AlphaMissense: likely pathogenic (0.8567); Very rare (popmax 0.00667%, amr).

How common is DTX4 p.His490Pro (c.1469A>C) in the general population?

DTX4 p.His490Pro (c.1469A>C) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about DTX4 p.His490Pro (c.1469A>C)?

AlphaMissense predicts likely pathogenic (score 0.8567) — an in-silico prediction, not a clinical call.

DTX4 p.His490Pro

c.1469A>C · VCV4662418

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8567 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8567	likely pathogenic
REVEL	0.455	indeterminate
SaProt	LLR -10.36	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.8, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 32 kb · p 2.6e-05 · regional, not allelic
Overall
CADD	28.9	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 0.00667% Admixed American · 4/59,940 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000248% 4/1,613,240 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: DTX4
Protein: p.His490Pro
Coding: c.1469A>C
MANE Select: NM_015177
Type: single nucleotide variant
Location: chr11:59195302 (GRCh38)
Gene constraint: LOEUF 0.732 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.83

Full DTX4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DTX4 p.Ala342= Benign ★★ same type
DTX4 p.Thr284= Benign ★★ same type
DTX4 p.Val257Gly Benign ★★ same type
DTX4 p.Val355= Benign ★★ same type
DTX4 p.Ala171Thr Uncertain significance ★ ⚠ same type
DTX4 p.Ala288Pro Uncertain significance ★ ⚠ same type
DTX4 p.Ala303Gly Uncertain significance ★ ⚠ same type
DTX4 p.Ala310Thr Uncertain significance ★ ⚠ same type

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/dtx4-p-his490pro (accessed [today's date]).

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