Is DNASE1 p.Val176= (c.528C>G) pathogenic?

DNASE1 p.Val176= (c.528C>G) is classified Benign in DNASE1 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-08-15). Low-frequency (popmax 4.61%, nfe).

How common is DNASE1 p.Val176= (c.528C>G) in the general population?

DNASE1 p.Val176= (c.528C>G) is low-frequency (popmax 4.61%, nfe) (gnomAD).

DNASE1 p.Val176=

c.528C>G · rs8176938 · VCV3059079

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

low-frequency (popmax 4.61%, 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
Pangolin	Δ0.30	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP -0.33	GERP -3.5
Overall
CADD	0.745	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.61% European (non-Finnish) · 54,415/1,180,004 alleles

Filtering AF 4.58% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.57%

Overall 4% 64,508/1,614,074 alleles · low-frequency

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	8.68%	12
European (non-Finnish)grpmax	4.61%	22
Admixed American	3.91%	26
Remaining individualsnot grpmax-eligible	3.77%	26
Finnishnot grpmax-eligible	3.34%	30
South Asian	2.23%	45
Middle Eastern	2.11%	47
Ashkenazi Jewishnot grpmax-eligible	1.56%	64
African / African-American	0.722%	138
East Asian	0.0267%	3,741

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val176=
Coding: c.528C>G
MANE Select: NM_005223
dbSNP: rs8176938
Type: single nucleotide variant
Location: chr16:3657090 (GRCh38)
Gene constraint: LOEUF 1.46 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 94.68 · 1 PDB
Residue 176: an α-helix

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

Similar variants

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
TRAP1 p.Ala676Val 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-val176 (accessed [today's date]).

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