Is DNASE2 p.Met110Ile (c.330G>A) pathogenic?

DNASE2 p.Met110Ile (c.330G>A) is classified Uncertain significance in DNASE2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-10). AlphaMissense: likely benign (0.1443); Very rare (popmax 8.47e-05%, nfe); Associated with DNASE2-related disorder.

What condition is associated with DNASE2 p.Met110Ile (c.330G>A)?

DNASE2 p.Met110Ile (c.330G>A) is associated with DNASE2-related disorder (ClinVar).

How common is DNASE2 p.Met110Ile (c.330G>A) in the general population?

DNASE2 p.Met110Ile (c.330G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about DNASE2 p.Met110Ile (c.330G>A)?

AlphaMissense predicts likely benign (score 0.1443) — an in-silico prediction, not a clinical call.

DNASE2 p.Met110Ile

c.330G>A · rs1378476377 · VCV2628708

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1443 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

DNASE2-related disorder

Computational evidence

Protein change
AlphaMissense	0.1443	likely benign
REVEL	0.015	strongly benign-leaning
SaProt	LLR -5.92	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 0.093	GERP -3, phastCons 0.002
Regional constraint	o/e 0.91	unconstrained · MANE · 5,382 bp · p 0.057 · regional, not allelic
Overall
CADD	0.378	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 8.47e-05% European (non-Finnish) · 1/1,180,044 alleles

Overall 6.84e-05% 1/1,461,888 alleles · very rare

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.Met110Ile
Coding: c.330G>A
MANE Select: NM_001375
dbSNP: rs1378476377
Type: single nucleotide variant
Location: chr19:12880818 (GRCh38)
Gene constraint: LOEUF 1.195 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.52
Residue 110: a disulfide bond

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

Disease context

DNASE2-related disorder

Similar variants

DNASE2 p.Met110Arg Uncertain significance ★ ⚠ same residue
DNASE2 c.709+4A>T Uncertain significance ★★ same condition
DNASE2 p.Gln155Glu Uncertain significance ★ ⚠ same condition
DNASE2 p.Gly24Glu Uncertain significance ★ ⚠ same condition
DNASE2 p.Ile360Ser Conflicting classifications of pathogenicity ★ ⚠ same condition
DNASE2 p.Ala332Asp Uncertain significance ★★ ⚠ same type
DNASE2 p.Arg321Trp Uncertain significance ★★ ⚠ same type
DNASE2 p.Asn69Ser 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-met110ile (accessed [today's date]).

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