Is DNASE1 p.Arg2Ser (c.6G>T) pathogenic?

DNASE1 p.Arg2Ser (c.6G>T) is classified Benign in DNASE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-09). AlphaMissense: likely benign (0.1739); Common (popmax 10.6%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about DNASE1 p.Arg2Ser (c.6G>T)?

AlphaMissense predicts likely benign (score 0.1739) — an in-silico prediction, not a clinical call.

DNASE1 p.Arg2Ser

Q: How common is DNASE1 p.Arg2Ser (c.6G>T) in the general population?

DNASE1 p.Arg2Ser (c.6G>T) is common (popmax 10.6%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.6G>T · VCV4684069

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1739 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 10.6%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1739	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -5.73	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 0.2	GERP -2.6
Regional constraint	o/e 1.39	unconstrained · MANE · 2,576 bp · p 4.9e-14 · regional, not allelic
Overall
CADD	5.839	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 10.6% African / African-American · 7,954/75,056 alleles

Filtering AF 10.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 10.3%

Overall 0.965% 15,572/1,614,140 alleles · common exomes 10,419/1,461,804 · genomes 5,153/152,336 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	10.6%	9
Middle Eastern	3.5%	29
Ashkenazi Jewishnot grpmax-eligible	2.09%	48
Admixed American	1.63%	61
Remaining individualsnot grpmax-eligible	1.48%	68
South Asian	1.06%	94
European (non-Finnish)	0.33%	303
Finnishnot grpmax-eligible	0.0328%	3,046
East Asian	0.00446%	22,444

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.Arg2Ser
Coding: c.6G>T
MANE Select: NM_005223
Type: single nucleotide variant
Location: chr16:3655379 (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.Arg2Trp Uncertain significance ★ ⚠ 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-arg2ser (accessed [today's date]).

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