Is DNASE2B p.Ile172Met (c.516A>G) pathogenic?

DNASE2B p.Ile172Met (c.516A>G) is classified Uncertain significance in DNASE2B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-14). AlphaMissense: likely benign (0.1145); Ultra-rare (popmax 0.0201%, eas).

How common is DNASE2B p.Ile172Met (c.516A>G) in the general population?

DNASE2B p.Ile172Met (c.516A>G) is ultra-rare (popmax 0.0201%, eas) (gnomAD).

What do computational predictors say about DNASE2B p.Ile172Met (c.516A>G)?

AlphaMissense predicts likely benign (score 0.1145) — an in-silico prediction, not a clinical call.

DNASE2B p.Ile172Met

c.516A>G · rs747665428 · VCV3084637

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1145 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1145	likely benign
REVEL	0.248	benign-leaning
SaProt	LLR -9.10	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 0.62	GERP -2.4, phastCons 0.92
Regional constraint	o/e 0.95	unconstrained · MANE · 16 kb · p 0.34 · regional, not allelic
Overall
CADD	16.0	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 0.0201% East Asian · 9/44,844 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0078%

Overall 0.000682% 11/1,612,008 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0201%	4,983
Remaining individualsnot grpmax-eligible	0.0032%	31,207

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: DNASE2B
Protein: p.Ile172Met
Coding: c.516A>G
MANE Select: NM_021233
dbSNP: rs747665428
Type: single nucleotide variant
Location: chr1:84410968 (GRCh38)
Gene constraint: LOEUF 1.21 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.22

Full DNASE2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DNASE2B p.Ala216Thr Uncertain significance ★ ⚠ same type
DNASE2B p.Arg270Gln Uncertain significance ★ ⚠ same type
DNASE2B p.Arg327Gln Uncertain significance ★ ⚠ same type
DNASE2B p.Asn104Thr Uncertain significance ★ ⚠ same type
DNASE2B p.Asn111Thr Uncertain significance ★ ⚠ same type
DNASE2B p.Asn278Ile Uncertain significance ★ ⚠ same type
DNASE2B p.Asn287Ser Uncertain significance ★ ⚠ same type
DNASE2B p.Asp244Val 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/dnase2b-p-ile172met (accessed [today's date]).

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