Is DNASE1 p.Arg2Trp (c.4A>T) pathogenic?

DNASE1 p.Arg2Trp (c.4A>T) is classified Uncertain significance in DNASE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-15). AlphaMissense: likely benign (0.204); Very rare (popmax 0.00549%, sas).

How common is DNASE1 p.Arg2Trp (c.4A>T) in the general population?

DNASE1 p.Arg2Trp (c.4A>T) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about DNASE1 p.Arg2Trp (c.4A>T)?

AlphaMissense predicts likely benign (score 0.204) — an in-silico prediction, not a clinical call.

DNASE1 p.Arg2Trp

c.4A>T · VCV4661444

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.204 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.204	likely benign
REVEL	0.199	benign-leaning
SaProt	LLR -7.74	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 1.6	GERP 1.1, phastCons 0.3
Regional constraint	o/e 1.39	unconstrained · MANE · 2,576 bp · p 4.9e-14 · regional, not allelic
Overall
CADD	16.07	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 0.00549% South Asian · 5/91,088 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000372% 6/1,613,954 alleles · very rare exomes 5/1,461,796 · genomes 1/152,158 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,218
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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: DNASE1
Protein: p.Arg2Trp
Coding: c.4A>T
MANE Select: NM_005223
Type: single nucleotide variant
Location: chr16:3655377 (GRCh38)
Gene constraint: LOEUF 1.46 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 94.68 · 1 PDB
Residue 2: a UniProt-annotated variant site (in)

Full DNASE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DNASE1 p.Arg2Ser Benign ★ same residue
DNASE1 p.Asn40Ser Uncertain significance ★★ ⚠ same type
DNASE1 p.Val21Met Uncertain significance ★★ ⚠ same type
TRAP1 p.Ala465Gly Uncertain significance ★★ ⚠ same type
TRAP1 p.Ala474Val Uncertain significance ★★ ⚠ same type
TRAP1 p.Ala608Ser Uncertain significance ★★ ⚠ same type
TRAP1 p.Ala628Val Uncertain significance ★★ ⚠ same type
TRAP1 p.Ala659Val 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/dnase1-p-arg2trp (accessed [today's date]).

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