Is DNASE1 p.Ala164Val (c.491C>T) pathogenic?

DNASE1 p.Ala164Val (c.491C>T) is classified Uncertain significance in DNASE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: likely benign (0.101); Very rare (popmax 0.00483%, nfe).

How common is DNASE1 p.Ala164Val (c.491C>T) in the general population?

DNASE1 p.Ala164Val (c.491C>T) is very rare (popmax 0.00483%, nfe) (gnomAD).

What do computational predictors say about DNASE1 p.Ala164Val (c.491C>T)?

AlphaMissense predicts likely benign (score 0.101) — an in-silico prediction, not a clinical call.

DNASE1 p.Ala164Val

c.491C>T · VCV4243351

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.101 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00483%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.101	likely benign
REVEL	0.129	moderately benign-leaning
SaProt	LLR -8.45	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 1.1	GERP 0.58, phastCons 0.001
Regional constraint	o/e 1.39	unconstrained · MANE · 2,576 bp · p 4.9e-14 · regional, not allelic
Overall
CADD	14.71	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 0.00483% European (non-Finnish) · 57/1,180,010 alleles

Filtering AF 0.00377% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00345%

Overall 0.00366% 59/1,613,884 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,803
European (non-Finnish)grpmax	0.00483%	20,702

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala164Val
Coding: c.491C>T
MANE Select: NM_005223
Type: single nucleotide variant
Location: chr16:3657053 (GRCh38)
Gene constraint: LOEUF 1.46 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 94.68 · 1 PDB
Residue 164: an α-helix

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

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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-ala164val (accessed [today's date]).

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