Is DNASE1 p.Val185Ile (c.553G>A) pathogenic?

DNASE1 p.Val185Ile (c.553G>A) is classified Likely benign in DNASE1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-03-01). AlphaMissense: likely benign (0.0696); Rare (popmax 0.67%, nfe).

How common is DNASE1 p.Val185Ile (c.553G>A) in the general population?

DNASE1 p.Val185Ile (c.553G>A) is rare (popmax 0.67%, nfe) (gnomAD).

What do computational predictors say about DNASE1 p.Val185Ile (c.553G>A)?

AlphaMissense predicts likely benign (score 0.0696) — an in-silico prediction, not a clinical call.

DNASE1 p.Val185Ile

c.553G>A · rs74892550 · VCV3024903

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0696 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.67%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0696	likely benign
REVEL	0.37	indeterminate
SaProt	LLR -6.77	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.6	GERP -3.5
Regional constraint	o/e 1.39	unconstrained · MANE · 2,576 bp · p 4.9e-14 · regional, not allelic
Overall
CADD	0.002	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

Grpmax group 0.67% European (non-Finnish) · 7,901/1,180,018 alleles

Filtering AF 0.657% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.652%

Overall 0.566% 9,143/1,614,106 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.09%	92
European (non-Finnish)grpmax	0.67%	149
Remaining individualsnot grpmax-eligible	0.642%	156
Admixed American	0.105%	953
African / African-American	0.0946%	1,057
Ashkenazi Jewishnot grpmax-eligible	0.0304%	3,290
South Asian	0.00329%	30,363
East Asian	0.00223%	44,876

Finnish 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.Val185Ile
Coding: c.553G>A
MANE Select: NM_005223
dbSNP: rs74892550
Type: single nucleotide variant
Location: chr16:3657190 (GRCh38)
Gene constraint: LOEUF 1.46 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 94.68 · 1 PDB
Residue 185: a β-strand

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

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TRAP1 p.Ala608Ser Uncertain significance ★★ ⚠ same type
TRAP1 p.Ala628Val Uncertain significance ★★ ⚠ same type
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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-val185ile (accessed [today's date]).

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