Is DNASE2B p.His208Pro (c.623A>C) pathogenic?

DNASE2B p.His208Pro (c.623A>C) is classified Uncertain significance in DNASE2B (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-25). AlphaMissense: likely benign (0.1439); Very rare (popmax 0.0011%, nfe).

How common is DNASE2B p.His208Pro (c.623A>C) in the general population?

DNASE2B p.His208Pro (c.623A>C) is very rare (popmax 0.0011%, nfe) (gnomAD).

What do computational predictors say about DNASE2B p.His208Pro (c.623A>C)?

AlphaMissense predicts likely benign (score 0.1439) — an in-silico prediction, not a clinical call.

DNASE2B p.His208Pro

c.623A>C · rs1301014846 · VCV2318955

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1439 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1439	likely benign
REVEL	0.155	moderately benign-leaning
SaProt	LLR -11.46	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 1.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 16 kb · p 0.34 · regional, not allelic
Overall
CADD	19.25	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 0.0011% European (non-Finnish) · 13/1,179,600 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.00089% 13/1,461,138 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: DNASE2B
Protein: p.His208Pro
Coding: c.623A>C
MANE Select: NM_021233
dbSNP: rs1301014846
Type: single nucleotide variant
Location: chr1:84412424 (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-his208pro (accessed [today's date]).

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