Is DTX2 p.Arg174His (c.521G>A) pathogenic?

DTX2 p.Arg174His (c.521G>A) is classified Uncertain significance in DTX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-17). AlphaMissense: likely benign (0.2371); Very rare (popmax 0.00178%, nfe).

How common is DTX2 p.Arg174His (c.521G>A) in the general population?

DTX2 p.Arg174His (c.521G>A) is very rare (popmax 0.00178%, nfe) (gnomAD).

What do computational predictors say about DTX2 p.Arg174His (c.521G>A)?

AlphaMissense predicts likely benign (score 0.2371) — an in-silico prediction, not a clinical call.

DTX2 p.Arg174His

c.521G>A · rs1474475420 · VCV3086113

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2371 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00178%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2371	likely benign
REVEL	0.746	pathogenic-leaning
SaProt	LLR -9.62	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	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	27.2	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00178% European (non-Finnish) · 21/1,179,814 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.00144% 21/1,461,592 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: DTX2
Protein: p.Arg174His
Coding: c.521G>A
MANE Select: NM_001102594
dbSNP: rs1474475420
Type: single nucleotide variant
Location: chr7:76482760 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.01 · 4 PDB
Residue 174: the wwe 2 domain

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

Similar variants

DTX2 p.Arg174Cys Uncertain significance ★ ⚠ same residue
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

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-arg174his (accessed [today's date]).

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