Is DNASE2 p.Ile360Ser (c.1079T>G) pathogenic?

DNASE2 p.Ile360Ser (c.1079T>G) is classified Conflicting classifications of pathogenicity in DNASE2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-12-19). AlphaMissense: likely benign (0.1085); Ultra-rare (popmax 0.0439%, sas); Associated with DNASE2-related disorder.

What condition is associated with DNASE2 p.Ile360Ser (c.1079T>G)?

DNASE2 p.Ile360Ser (c.1079T>G) is associated with DNASE2-related disorder (ClinVar).

How common is DNASE2 p.Ile360Ser (c.1079T>G) in the general population?

DNASE2 p.Ile360Ser (c.1079T>G) is ultra-rare (popmax 0.0439%, sas) (gnomAD).

What do computational predictors say about DNASE2 p.Ile360Ser (c.1079T>G)?

AlphaMissense predicts likely benign (score 0.1085) — an in-silico prediction, not a clinical call.

DNASE2 p.Ile360Ser

c.1079T>G · rs554384572 · VCV1063143

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1085 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0439%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

DNASE2-related disorder

Computational evidence

Protein change
AlphaMissense	0.1085	likely benign
REVEL	0.028	moderately benign-leaning
SaProt	LLR -4.97	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 -0.29	GERP -1.1, phastCons 0.002
Regional constraint	o/e 0.91	unconstrained · MANE · 5,382 bp · p 0.057 · regional, not allelic
Overall
CADD	1.343	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 0.0439% South Asian · 40/91,044 alleles

Filtering AF 0.0331% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0293%

Overall 0.00353% 57/1,613,124 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0439%	2,276
African / African-American	0.008%	12,500
Remaining individualsnot grpmax-eligible	0.0016%	62,432
European (non-Finnish)	0.000847%	118,000

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: DNASE2
Protein: p.Ile360Ser
Coding: c.1079T>G
MANE Select: NM_001375
dbSNP: rs554384572
Type: single nucleotide variant
Location: chr19:12875994 (GRCh38)
Gene constraint: LOEUF 1.195 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.52

Full DNASE2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

DNASE2-related disorder

Similar variants

DNASE2 c.709+4A>T Uncertain significance ★★ same condition
DNASE2 p.Met110Ile Uncertain significance ★★ ⚠ same condition
DNASE2 p.Gln155Glu Uncertain significance ★ ⚠ same condition
DNASE2 p.Gly24Glu Uncertain significance ★ ⚠ same condition
DNASE2 p.Ala332Asp Uncertain significance ★★ ⚠ same type
DNASE2 p.Arg321Trp Uncertain significance ★★ ⚠ same type
DNASE2 p.Asn69Ser Uncertain significance ★★ ⚠ same type
DNASE2 p.Cys159Trp 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/dnase2-p-ile360ser (accessed [today's date]).

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