Is DTX2 p.Ala422= (c.1266G>A) pathogenic?

DTX2 p.Ala422= (c.1266G>A) is classified Likely benign in DTX2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). Common (popmax 44%, eas) — too common for a highly-penetrant pathogenic allele.

DTX2 p.Ala422=

Q: How common is DTX2 p.Ala422= (c.1266G>A) in the general population?

DTX2 p.Ala422= (c.1266G>A) is common (popmax 44%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1266G>A · rs6958774 · VCV768164

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 44%, eas) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.1	GERP -3.7
Overall
CADD	0.397	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 44% East Asian · 19,545/44,430 alleles

Filtering AF 43.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 43.3%

Overall 37.8% 582,488/1,539,280 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	51.7%	2
East Asiangrpmax	44%	2
Amishnot grpmax-eligible	39.3%	3
European (non-Finnish)	38.7%	3
Remaining individualsnot grpmax-eligible	36.9%	3
Admixed American	36.2%	3
South Asian	32.7%	3
Ashkenazi Jewishnot grpmax-eligible	30.5%	3
Middle Eastern	24.9%	4
African / African-American	21.6%	5

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala422=
Coding: c.1266G>A
MANE Select: NM_001102594
dbSNP: rs6958774
Type: single nucleotide variant
Location: chr7:76502333 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.01 · 4 PDB

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

Similar variants

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
DTX2 p.Ala258Val 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-ala422 (accessed [today's date]).

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