Is DNASE1 p.Ile56= (c.168C>T) pathogenic?

DNASE1 p.Ile56= (c.168C>T) is classified Likely benign in DNASE1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-06-05). Rare (popmax 0.12%, sas); Associated with DNASE1-related disorder.

What condition is associated with DNASE1 p.Ile56= (c.168C>T)?

DNASE1 p.Ile56= (c.168C>T) is associated with DNASE1-related disorder (ClinVar).

How common is DNASE1 p.Ile56= (c.168C>T) in the general population?

DNASE1 p.Ile56= (c.168C>T) is rare (popmax 0.12%, sas) (gnomAD).

DNASE1 p.Ile56=

c.168C>T · rs557122880 · VCV3044569

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.12%, sas)

Conditions

DNASE1-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.25	acceptor loss, 20 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -9.9	GERP -4.2
Overall
CADD	0.287	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.12% South Asian · 109/91,084 alleles

Filtering AF 0.101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0946%

Overall 0.00899% 145/1,613,568 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.12%	836
Middle Eastern	0.0165%	6,050
Remaining individualsnot grpmax-eligible	0.008%	12,500
African / African-American	0.00666%	15,012
Admixed American	0.005%	20,000
European (non-Finnish)	0.00186%	53,623

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.Ile56=
Coding: c.168C>T
MANE Select: NM_005223
dbSNP: rs557122880
Type: single nucleotide variant
Location: chr16:3655869 (GRCh38)
Gene constraint: LOEUF 1.46 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 94.68 · 1 PDB
Residue 56: a β-strand

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

Disease context

DNASE1-related disorder

Similar variants

TRAP1 p.Glu471Lys Uncertain significance ★★ ⚠ same condition
TRAP1 p.Ala649Thr Conflicting classifications of pathogenicity ★ ⚠ same condition
TRAP1 p.Pro686Arg Uncertain significance ★ ⚠ same condition
DNASE1 p.Asn78Thr Uncertain significance ⚠ same condition
DNASE1 p.Asp167= Likely benign same condition
DNASE1 p.Cys126= Likely benign same condition
DNASE1 p.Thr42= Likely benign same condition
TRAP1 c.1940+8C>T Likely benign same condition

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-ile56 (accessed [today's date]).

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