Is DNASE2 p.Ala332Asp (c.995C>A) pathogenic?

DNASE2 p.Ala332Asp (c.995C>A) is classified Uncertain significance in DNASE2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-23). AlphaMissense: likely benign (0.1166); Rare (popmax 0.197%, afr); Associated with autoinflammatory-pancytopenia syndrome due to DNASE2 deficiency.

What condition is associated with DNASE2 p.Ala332Asp (c.995C>A)?

DNASE2 p.Ala332Asp (c.995C>A) is associated with autoinflammatory-pancytopenia syndrome due to DNASE2 deficiency (ClinVar).

How common is DNASE2 p.Ala332Asp (c.995C>A) in the general population?

DNASE2 p.Ala332Asp (c.995C>A) is rare (popmax 0.197%, afr) (gnomAD).

What do computational predictors say about DNASE2 p.Ala332Asp (c.995C>A)?

AlphaMissense predicts likely benign (score 0.1166) — an in-silico prediction, not a clinical call.

DNASE2 p.Ala332Asp

c.995C>A · rs138534991 · VCV1493258

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1166 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.197%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autoinflammatory-pancytopenia syndrome due to DNASE2 deficiency

Computational evidence

Protein change
AlphaMissense	0.1166	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -7.43	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 3.4	GERP -2.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 5,382 bp · p 0.057 · regional, not allelic
Overall
CADD	18.79	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 0.197% African / African-American · 148/75,044 alleles

Filtering AF 0.171% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.161%

Overall 0.011% 178/1,613,926 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.197%	507
Admixed American	0.02%	5,002
Remaining individualsnot grpmax-eligible	0.0176%	5,682
Middle Eastern	0.0166%	6,034
South Asian	0.00549%	18,216
European (non-Finnish)	8.47e-05%	1,179,993

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: DNASE2
Protein: p.Ala332Asp
Coding: c.995C>A
MANE Select: NM_001375
dbSNP: rs138534991
Type: single nucleotide variant
Location: chr19:12876078 (GRCh38)
Gene constraint: LOEUF 1.195 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.52
Residue 332: a disulfide bond

Full DNASE2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autoinflammatory-pancytopenia syndrome due to DNASE2 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DNASE2 p.Ala332= Likely benign ★ same residue
DNASE2 p.Tyr53His Uncertain significance ★ ⚠ same condition
DNASE2 p.Asp121Val Pathogenic same condition
DNASE2 p.Gly116Ala Pathogenic same condition
DNASE2 p.Tyr95Cys Pathogenic same condition
DNASE2 c.709+4A>T Uncertain significance ★★ same type
DNASE2 p.Arg321Trp Uncertain significance ★★ ⚠ same type
DNASE2 p.Asn69Ser 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/dnase2-p-ala332asp (accessed [today's date]).

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