Is DNASE2 p.Val309Met (c.925G>A) pathogenic?

DNASE2 p.Val309Met (c.925G>A) is classified Uncertain significance in DNASE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-27). AlphaMissense: likely benign (0.2121); Very rare (popmax 0.00446%, eas).

How common is DNASE2 p.Val309Met (c.925G>A) in the general population?

DNASE2 p.Val309Met (c.925G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about DNASE2 p.Val309Met (c.925G>A)?

AlphaMissense predicts likely benign (score 0.2121) — an in-silico prediction, not a clinical call.

DNASE2 p.Val309Met

c.925G>A · rs747693624 · VCV1349577

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2121 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2121	likely benign
REVEL	0.276	benign-leaning
SaProt	LLR -10.41	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -1, phastCons 0.98
Regional constraint	o/e 0.91	unconstrained · MANE · 5,382 bp · p 0.057 · regional, not allelic
Overall
CADD	22.6	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 0.00446% East Asian · 2/44,888 alleles

Filtering AF 0.00215% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00191%

Overall 0.0026% 42/1,614,236 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,444
Remaining individualsnot grpmax-eligible	0.0032%	31,255
European (non-Finnish)	0.00297%	33,716
South Asian	0.0022%	45,544
African / African-American	0.00133%	75,072

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.Val309Met
Coding: c.925G>A
MANE Select: NM_001375
dbSNP: rs747693624
Type: single nucleotide variant
Location: chr19:12876148 (GRCh38)
Gene constraint: LOEUF 1.195 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.52
Residue 309: a disulfide bond

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

Similar variants

DNASE2 p.Val309Leu Uncertain significance ★ ⚠ same residue
DNASE2 c.709+4A>T Uncertain significance ★★ same type
DNASE2 p.Ala332Asp 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
DNASE2 p.Glu43Gly Uncertain significance ★★ ⚠ same type
DNASE2 p.Gly241Ser 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-val309met (accessed [today's date]).

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