Is DNASE1 p.Arg53His (c.158G>A) pathogenic?

DNASE1 p.Arg53His (c.158G>A) is classified Uncertain significance in DNASE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-22). AlphaMissense: likely benign (0.1139); Very rare (popmax 0.0022%, sas).

How common is DNASE1 p.Arg53His (c.158G>A) in the general population?

DNASE1 p.Arg53His (c.158G>A) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about DNASE1 p.Arg53His (c.158G>A)?

AlphaMissense predicts likely benign (score 0.1139) — an in-silico prediction, not a clinical call.

DNASE1 p.Arg53His

c.158G>A · VCV4830332

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1139 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1139	likely benign
REVEL	0.219	benign-leaning
SaProt	LLR -10.90	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.4	GERP 1.1, phastCons 1
Regional constraint	o/e 1.39	unconstrained · MANE · 2,576 bp · p 4.9e-14 · regional, not allelic
Overall
CADD	21.3	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 0.0022% South Asian · 2/91,086 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000868% 14/1,613,300 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,543
Admixed American	0.00167%	59,976
European (non-Finnish)	0.000932%	107,247

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.Arg53His
Coding: c.158G>A
MANE Select: NM_005223
Type: single nucleotide variant
Location: chr16:3655859 (GRCh38)
Gene constraint: LOEUF 1.46 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 94.68 · 1 PDB

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

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TRAP1 p.Ala608Ser Uncertain significance ★★ ⚠ same type
TRAP1 p.Ala628Val Uncertain significance ★★ ⚠ same type
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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-arg53his (accessed [today's date]).

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