Is DNASE2 p.Pro339Leu (c.1016C>T) pathogenic?

DNASE2 p.Pro339Leu (c.1016C>T) is classified Uncertain significance in DNASE2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-18). AlphaMissense: likely benign (0.1216); Ultra-rare (popmax 0.0549%, sas).

How common is DNASE2 p.Pro339Leu (c.1016C>T) in the general population?

DNASE2 p.Pro339Leu (c.1016C>T) is ultra-rare (popmax 0.0549%, sas) (gnomAD).

What do computational predictors say about DNASE2 p.Pro339Leu (c.1016C>T)?

AlphaMissense predicts likely benign (score 0.1216) — an in-silico prediction, not a clinical call.

DNASE2 p.Pro339Leu

c.1016C>T · rs375137579 · VCV1346441

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1216 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0549%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1216	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	LLR -10.20	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 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 5,382 bp · p 0.057 · regional, not allelic
Overall
CADD	23.5	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 0.0549% South Asian · 50/91,080 alleles

Filtering AF 0.0427% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0385%

Overall 0.0044% 71/1,613,928 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0549%	1,822
Middle Eastern	0.0166%	6,008
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600
East Asian	0.00223%	44,884
European (non-Finnish)	0.00153%	65,557

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.Pro339Leu
Coding: c.1016C>T
MANE Select: NM_001375
dbSNP: rs375137579
Type: single nucleotide variant
Location: chr19:12876057 (GRCh38)
Gene constraint: LOEUF 1.195 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.52
Residue 339: a disulfide bond

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

Similar variants

DNASE2 p.Pro339= Likely benign ★★ same residue
DNASE2 p.Pro339Gln 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

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-pro339leu (accessed [today's date]).

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