Is DNASE2 p.Ala142Val (c.425C>T) pathogenic?

DNASE2 p.Ala142Val (c.425C>T) is classified Uncertain significance in DNASE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-12-26). AlphaMissense: likely benign (0.1013); Very rare (popmax 0.000339%, nfe).

How common is DNASE2 p.Ala142Val (c.425C>T) in the general population?

DNASE2 p.Ala142Val (c.425C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about DNASE2 p.Ala142Val (c.425C>T)?

AlphaMissense predicts likely benign (score 0.1013) — an in-silico prediction, not a clinical call.

DNASE2 p.Ala142Val

c.425C>T · rs1221678470 · VCV1467114

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1013 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1013	likely benign
REVEL	0.016	strongly benign-leaning
SaProt	LLR -7.90	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.36	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 0.67	GERP -2.8
Regional constraint	o/e 0.91	unconstrained · MANE · 5,382 bp · p 0.057 · regional, not allelic
Overall
CADD	11.98	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 0.000339% European (non-Finnish) · 4/1,180,012 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,986 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.Ala142Val
Coding: c.425C>T
MANE Select: NM_001375
dbSNP: rs1221678470
Type: single nucleotide variant
Location: chr19:12878756 (GRCh38)
Gene constraint: LOEUF 1.195 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.52
Residue 142: a disulfide bond

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

Similar variants

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
DNASE2 p.Gly286Ser 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-ala142val (accessed [today's date]).

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