Is DNASE2 p.Ser141Pro (c.421T>C) pathogenic?

DNASE2 p.Ser141Pro (c.421T>C) is classified Uncertain significance in DNASE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-29). AlphaMissense: likely benign (0.1438); Absent from gnomAD v4.1.

How common is DNASE2 p.Ser141Pro (c.421T>C) in the general population?

DNASE2 p.Ser141Pro (c.421T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DNASE2 p.Ser141Pro (c.421T>C)?

AlphaMissense predicts likely benign (score 0.1438) — an in-silico prediction, not a clinical call.

DNASE2 p.Ser141Pro

c.421T>C · rs2512549745 · VCV2000500

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1438 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1438	likely benign
REVEL	0.051	moderately benign-leaning
SaProt	LLR -10.68	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.22	GERP -0.97
Regional constraint	o/e 0.91	unconstrained · MANE · 5,382 bp · p 0.057 · regional, not allelic
Overall
CADD	15.53	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

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.Ser141Pro
Coding: c.421T>C
MANE Select: NM_001375
dbSNP: rs2512549745
Type: single nucleotide variant
Location: chr19:12878760 (GRCh38)
Gene constraint: LOEUF 1.195 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.52
Residue 141: 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-ser141pro (accessed [today's date]).

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