Is DNASE1 p.Pro154Ala (c.460C>G) pathogenic?

DNASE1 p.Pro154Ala (c.460C>G) is classified Benign in DNASE1 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-04-24). AlphaMissense: likely benign (0.1778); Low-frequency (popmax 2.79%, amr).

How common is DNASE1 p.Pro154Ala (c.460C>G) in the general population?

DNASE1 p.Pro154Ala (c.460C>G) is low-frequency (popmax 2.79%, amr) (gnomAD).

What do computational predictors say about DNASE1 p.Pro154Ala (c.460C>G)?

AlphaMissense predicts likely benign (score 0.1778) — an in-silico prediction, not a clinical call.

DNASE1 p.Pro154Ala

c.460C>G · rs1799891 · VCV3035786

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1778 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.79%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1778	likely benign
REVEL	0.371	indeterminate
SaProt	LLR -8.94	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 1.8, phastCons 0.91
Regional constraint	o/e 1.39	unconstrained · MANE · 2,576 bp · p 4.9e-14 · regional, not allelic
Overall
CADD	20.5	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 2.79% Admixed American · 1,673/60,008 alleles

Filtering AF 2.68% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.63%

Overall 0.165% 2,665/1,613,764 alleles · low-frequency

Ancestry group	Frequency	1 in
Admixed Americangrpmax	2.79%	36
East Asian	1.59%	63
South Asian	0.152%	660
Remaining individualsnot grpmax-eligible	0.128%	781
African / African-American	0.0293%	3,410
European (non-Finnish)	0.00339%	29,499

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: DNASE1
Protein: p.Pro154Ala
Coding: c.460C>G
MANE Select: NM_005223
dbSNP: rs1799891
Type: single nucleotide variant
Location: chr16:3657022 (GRCh38)
Gene constraint: LOEUF 1.46 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 94.68 · 1 PDB
Residue 154: a UniProt-annotated variant site (in allele dnase1*3); a β-strand

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

Similar variants

DNASE1 p.Asn40Ser Uncertain significance ★★ ⚠ same type
DNASE1 p.Val21Met Uncertain significance ★★ ⚠ same type
TRAP1 p.Ala465Gly Uncertain significance ★★ ⚠ same type
TRAP1 p.Ala474Val Uncertain significance ★★ ⚠ same type
TRAP1 p.Ala608Ser Uncertain significance ★★ ⚠ same type
TRAP1 p.Ala628Val Uncertain significance ★★ ⚠ same type
TRAP1 p.Ala659Val Uncertain significance ★★ ⚠ same type
TRAP1 p.Ala676Val 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-pro154ala (accessed [today's date]).

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