Is DNASE1L3 p.Pro142Ala (c.424C>G) pathogenic?

DNASE1L3 p.Pro142Ala (c.424C>G) is classified Uncertain significance in DNASE1L3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-27). AlphaMissense: likely benign (0.1463); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with DNASE1L3 p.Pro142Ala (c.424C>G)?

DNASE1L3 p.Pro142Ala (c.424C>G) is associated with Inborn genetic diseases (ClinVar).

How common is DNASE1L3 p.Pro142Ala (c.424C>G) in the general population?

DNASE1L3 p.Pro142Ala (c.424C>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about DNASE1L3 p.Pro142Ala (c.424C>G)?

AlphaMissense predicts likely benign (score 0.1463) — an in-silico prediction, not a clinical call.

DNASE1L3 p.Pro142Ala

c.424C>G · rs563166164 · VCV3084629

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1463 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1463	likely benign
REVEL	0.27	benign-leaning
SaProt	LLR -7.30	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 6.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 18 kb · p 0.46 · regional, not allelic
Overall
CADD	23.0	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 0.00223% East Asian · 1/44,890 alleles

Overall 6.84e-05% 1/1,461,826 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: DNASE1L3
Protein: p.Pro142Ala
Coding: c.424C>G
MANE Select: NM_004944
dbSNP: rs563166164
Type: single nucleotide variant
Location: chr3:58204778 (GRCh38)
Gene constraint: LOEUF 1.122 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.08 · 1 PDB

Full DNASE1L3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DNASE1L3 p.Pro142Thr Uncertain significance ★★ ⚠ same residue
DNASE1L3 p.Pro142= Likely benign ★ same residue
DNASE1L3 p.Ala18Thr Uncertain significance ★★ ⚠ same condition
DNASE1L3 p.Asp126Tyr Uncertain significance ★★ ⚠ same condition
DNASE1L3 p.Glu33Lys Uncertain significance ★★ ⚠ same condition
DNASE1L3 p.Ile49Val Uncertain significance ★★ ⚠ same condition
DNASE1L3 p.Leu12His Uncertain significance ★★ ⚠ same condition
DNASE1L3 p.Met21Val Uncertain significance ★★ ⚠ same condition

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/dnase1l3-p-pro142ala (accessed [today's date]).

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