Is DNASE1 p.Pro219Ser (c.655C>T) pathogenic?

DNASE1 p.Pro219Ser (c.655C>T) is classified Uncertain significance in DNASE1 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-04-08). AlphaMissense: likely benign (0.1247); Rare (popmax 0.192%, afr).

How common is DNASE1 p.Pro219Ser (c.655C>T) in the general population?

DNASE1 p.Pro219Ser (c.655C>T) is rare (popmax 0.192%, afr) (gnomAD).

What do computational predictors say about DNASE1 p.Pro219Ser (c.655C>T)?

AlphaMissense predicts likely benign (score 0.1247) — an in-silico prediction, not a clinical call.

DNASE1 p.Pro219Ser

c.655C>T · rs34186031 · VCV3034868

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1247 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.192%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1247	likely benign
REVEL	0.181	moderately benign-leaning
SaProt	LLR -8.69	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 2.6	GERP 0.53, phastCons 0.98
Regional constraint	o/e 1.39	unconstrained · MANE · 2,576 bp · p 4.9e-14 · regional, not allelic
Overall
CADD	17.44	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 0.192% African / African-American · 144/75,046 alleles

Filtering AF 0.166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.157%

Overall 0.01% 162/1,613,916 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.192%	521
Admixed American	0.0183%	5,455
Remaining individualsnot grpmax-eligible	0.0112%	8,930

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.Pro219Ser
Coding: c.655C>T
MANE Select: NM_005223
dbSNP: rs34186031
Type: single nucleotide variant
Location: chr16:3657292 (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.Pro219= Likely benign ★ 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-pro219ser (accessed [today's date]).

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