Is DTX2 p.Thr89Pro (c.265A>C) pathogenic?

DTX2 p.Thr89Pro (c.265A>C) is classified Uncertain significance in DTX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-27). AlphaMissense: likely pathogenic (0.9469); Ultra-rare (popmax 0.0155%, amr).

How common is DTX2 p.Thr89Pro (c.265A>C) in the general population?

DTX2 p.Thr89Pro (c.265A>C) is ultra-rare (popmax 0.0155%, amr) (gnomAD).

What do computational predictors say about DTX2 p.Thr89Pro (c.265A>C)?

AlphaMissense predicts likely pathogenic (score 0.9469) — an in-silico prediction, not a clinical call.

DTX2 p.Thr89Pro

c.265A>C · rs1359328082 · VCV3086109

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9469 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0155%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9469	likely pathogenic
REVEL	0.505	indeterminate
SaProt	LLR -17.16	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 1.7, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 2,592 bp · p 1.6e-06 · regional, not allelic
Overall
CADD	26.1	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 0.0155% Admixed American · 9/58,208 alleles

Filtering AF 0.00805% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00594%

Overall 0.000563% 9/1,598,440 alleles · ultra-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: DTX2
Protein: p.Thr89Pro
Coding: c.265A>C
MANE Select: NM_001102594
dbSNP: rs1359328082
Type: single nucleotide variant
Location: chr7:76480774 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.01 · 4 PDB
Residue 89: the wwe 1 domain

Full DTX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DTX2 p.Ala422= Likely benign ★★ same type
DTX2 p.Gly515= Likely benign ★★ same type
DTX2 p.Pro484= Benign ★★ same type
DTX2 p.Ala146Asp Uncertain significance ★ ⚠ same type
DTX2 p.Ala17Thr Uncertain significance ★ ⚠ same type
DTX2 p.Ala187Ser Uncertain significance ★ ⚠ same type
DTX2 p.Ala195Ser Uncertain significance ★ ⚠ same type
DTX2 p.Ala255Gly 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/dtx2-p-thr89pro (accessed [today's date]).

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