Is DNASE1 p.Pro219= (c.657C>T) pathogenic?

DNASE1 p.Pro219= (c.657C>T) is classified Likely benign in DNASE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-16). Ultra-rare (popmax 0.0187%, nfe).

How common is DNASE1 p.Pro219= (c.657C>T) in the general population?

DNASE1 p.Pro219= (c.657C>T) is ultra-rare (popmax 0.0187%, nfe) (gnomAD).

DNASE1 p.Pro219=

c.657C>T · VCV4684071

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -9.3	GERP -3.5
Overall
CADD	0.531	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0187% European (non-Finnish) · 221/1,180,028 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0159%

Overall 0.0149% 240/1,613,792 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0187%	5,339
Middle Eastern	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0128%	7,810
East Asian	0.00446%	22,445
South Asian	0.00439%	22,773
Finnishnot grpmax-eligible	0.00314%	31,887
Admixed American	0.00167%	60,004
African / African-American	0.00133%	74,924

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.Pro219=
Coding: c.657C>T
MANE Select: NM_005223
Type: single nucleotide variant
Location: chr16:3657294 (GRCh38)
Gene constraint: LOEUF 1.46 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 94.68 · 1 PDB
Residue 219: a disulfide bond

Full DNASE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DNASE1 p.Pro219Ser 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-pro219 (accessed [today's date]).

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