Is DTX2 p.Pro389Ala (c.1165C>G) pathogenic?

DTX2 p.Pro389Ala (c.1165C>G) is classified Uncertain significance in DTX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-22). AlphaMissense: likely benign (0.0545); Very rare (popmax 0.0028%, eas).

How common is DTX2 p.Pro389Ala (c.1165C>G) in the general population?

DTX2 p.Pro389Ala (c.1165C>G) is very rare (popmax 0.0028%, eas) (gnomAD).

What do computational predictors say about DTX2 p.Pro389Ala (c.1165C>G)?

AlphaMissense predicts likely benign (score 0.0545) — an in-silico prediction, not a clinical call.

DTX2 p.Pro389Ala

c.1165C>G · rs2536580292 · VCV2605665

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0545 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0028%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0545	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	LLR -7.21	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP -2.6, phastCons 1
Regional constraint	o/e 0.06	constrained · MANE · 10 kb · p 1.4e-18 · regional, not allelic
Overall
CADD	18.88	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0028% East Asian · 1/35,684 alleles

Overall 0.000132% 1/756,510 alleles · very rare exomes 1/640,542 · genomes 0/115,968 · joint denominator

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.Pro389Ala
Coding: c.1165C>G
MANE Select: NM_001102594
dbSNP: rs2536580292
Type: single nucleotide variant
Location: chr7:76500455 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.01 · 4 PDB
Residue 389: the 'disordered' region

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-pro389ala (accessed [today's date]).

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