Is DTX2 p.Arg535Cys (c.1603C>T) pathogenic?

DTX2 p.Arg535Cys (c.1603C>T) is classified Uncertain significance in DTX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-11). AlphaMissense: likely pathogenic (0.9804); Rare (popmax 0.162%, amr).

How common is DTX2 p.Arg535Cys (c.1603C>T) in the general population?

DTX2 p.Arg535Cys (c.1603C>T) is rare (popmax 0.162%, amr) (gnomAD).

What do computational predictors say about DTX2 p.Arg535Cys (c.1603C>T)?

AlphaMissense predicts likely pathogenic (score 0.9804) — an in-silico prediction, not a clinical call.

DTX2 p.Arg535Cys

c.1603C>T · rs746771647 · VCV2209334

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9804 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.162%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9804	likely pathogenic
REVEL	0.658	pathogenic-leaning
SaProt	LLR -12.63	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.83, phastCons 1
Regional constraint	o/e 0.00	constrained · MANE · 860 bp · p 4.5e-09 · regional, not allelic
Overall
CADD	32.0	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 0.162% Admixed American · 69/42,654 alleles

Filtering AF 0.131% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.12%

Overall 0.0291% 348/1,195,140 alleles · rare exomes 304/1,063,160 · genomes 44/131,980 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.162%	618
Remaining individualsnot grpmax-eligible	0.0331%	3,019
European (non-Finnish)	0.0299%	3,339
African / African-American	0.0079%	12,661
East Asian	0.00265%	37,788
South Asian	0.00136%	73,600

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.Arg535Cys
Coding: c.1603C>T
MANE Select: NM_001102594
dbSNP: rs746771647
Type: single nucleotide variant
Location: chr7:76504407 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.01 · 4 PDB
Residue 535: a β-strand

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-arg535cys (accessed [today's date]).

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