Is DNASE1 p.Val277Ala (c.830T>C) pathogenic?

DNASE1 p.Val277Ala (c.830T>C) is classified Uncertain significance in DNASE1 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely pathogenic (0.6869); Absent from gnomAD v4.1; Associated with systemic lupus erythematosus.

What condition is associated with DNASE1 p.Val277Ala (c.830T>C)?

DNASE1 p.Val277Ala (c.830T>C) is associated with systemic lupus erythematosus (ClinVar).

How common is DNASE1 p.Val277Ala (c.830T>C) in the general population?

DNASE1 p.Val277Ala (c.830T>C) is absent from gnomAD v4.1 (gnomAD).

How is Systemic lupus erythematosus inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about DNASE1 p.Val277Ala (c.830T>C)?

AlphaMissense predicts likely pathogenic (score 0.6869) — an in-silico prediction, not a clinical call.

DNASE1 p.Val277Ala

c.830T>C · VCV3391314

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6869 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

systemic lupus erythematosus

Computational evidence

Protein change
AlphaMissense	0.6869	likely pathogenic
REVEL	0.565	indeterminate
SaProt	LLR -11.42	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 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 1.39	unconstrained · MANE · 2,576 bp · p 4.9e-14 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DNASE1
Protein: p.Val277Ala
Coding: c.830T>C
MANE Select: NM_005223
Type: single nucleotide variant
Location: chr16:3657934 (GRCh38)
Gene constraint: LOEUF 1.46 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 94.68 · 1 PDB
Residue 277: a β-strand

Full DNASE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

systemic lupus erythematosus — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Systemic lupus erythematosus (Orphanet):

Inheritance: Not applicable
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-5 / 10 000 (France)

Similar variants

DNASE1 p.Gly127Arg Benign/Likely benign ★★ ⚠ same condition
DNASE1 p.Gln31Ter Likely pathogenic ★ same condition
DNASE1 p.Arg133Gln Uncertain significance ★ ⚠ same condition
DNASE1 p.Arg207Cys Conflicting classifications of pathogenicity ★ ⚠ same condition
DNASE1 p.Arg207His Uncertain significance ★ ⚠ same condition
DNASE1 p.Asp129Asn Uncertain significance ★ ⚠ same condition
DNASE1 p.Gln258fs Uncertain significance ★ same condition
DNASE1 p.Asn40Ser 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/dnase1-p-val277ala (accessed [today's date]).

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