Is DNASE2 p.Asp121Val (c.362A>T) pathogenic?

DNASE2 p.Asp121Val (c.362A>T) is classified Pathogenic in DNASE2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-04-29). AlphaMissense: likely pathogenic (0.6194); Very rare (popmax 8.48e-05%, nfe); Associated with autoinflammatory-pancytopenia syndrome due to DNASE2 deficiency.

What condition is associated with DNASE2 p.Asp121Val (c.362A>T)?

DNASE2 p.Asp121Val (c.362A>T) is associated with autoinflammatory-pancytopenia syndrome due to DNASE2 deficiency (ClinVar).

How common is DNASE2 p.Asp121Val (c.362A>T) in the general population?

DNASE2 p.Asp121Val (c.362A>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about DNASE2 p.Asp121Val (c.362A>T)?

AlphaMissense predicts likely pathogenic (score 0.6194) — an in-silico prediction, not a clinical call.

DNASE2 p.Asp121Val

c.362A>T · rs2145921549 · VCV1686900

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6194 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autoinflammatory-pancytopenia syndrome due to DNASE2 deficiency

Computational evidence

Protein change
AlphaMissense	0.6194	likely pathogenic ✓ concordant with ClinVar
REVEL	0.391	indeterminate
SaProt	LLR -15.25	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 0.42, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 5,382 bp · p 0.057 · regional, not allelic
Overall
CADD	22.5	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 8.48e-05% European (non-Finnish) · 1/1,179,808 alleles

Overall 6.84e-05% 1/1,460,960 alleles · very rare

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.Asp121Val
Coding: c.362A>T
MANE Select: NM_001375
dbSNP: rs2145921549
Type: single nucleotide variant
Location: chr19:12878819 (GRCh38)
Gene constraint: LOEUF 1.195 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.52
Residue 121: a UniProt-annotated variant site (in aipcs; reduced dnase activity); 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.Ala332Asp Uncertain significance ★★ ⚠ same condition
DNASE2 p.Tyr53His Uncertain significance ★ ⚠ 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
DNASE2 p.Cys159Trp 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-asp121val (accessed [today's date]).

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