Is DNASE2 p.Cys267Ser (c.800G>C) pathogenic?

DNASE2 p.Cys267Ser (c.800G>C) is classified Uncertain significance in DNASE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-03). AlphaMissense: likely pathogenic (0.8547); Absent from gnomAD v4.1.

How common is DNASE2 p.Cys267Ser (c.800G>C) in the general population?

DNASE2 p.Cys267Ser (c.800G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DNASE2 p.Cys267Ser (c.800G>C)?

AlphaMissense predicts likely pathogenic (score 0.8547) — an in-silico prediction, not a clinical call.

DNASE2 p.Cys267Ser

c.800G>C · rs2512547891 · VCV3084630

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8547 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8547	likely pathogenic · top 8% in DNASE2
REVEL	0.614	indeterminate
SaProt	LLR -14.12	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 5,382 bp · p 0.057 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DNASE2
Protein: p.Cys267Ser
Coding: c.800G>C
MANE Select: NM_001375
dbSNP: rs2512547891
Type: single nucleotide variant
Location: chr19:12876273 (GRCh38)
Gene constraint: LOEUF 1.195 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.52
Residue 267: a disulfide bond

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

Similar variants

DNASE2 c.709+4A>T Uncertain significance ★★ same type
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
DNASE2 p.Glu43Gly Uncertain significance ★★ ⚠ same type
DNASE2 p.Gly241Ser Uncertain significance ★★ ⚠ same type
DNASE2 p.Gly286Ser 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-cys267ser (accessed [today's date]).

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