Is NBN p.Pro174fs (c.520_521insT) pathogenic?

NBN p.Pro174fs (c.520521insT) is classified Pathogenic in NBN (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-29). Absent from gnomAD; Associated with Nijmegen breakage syndrome.

What condition is associated with NBN p.Pro174fs (c.520_521insT)?

NBN p.Pro174fs (c.520_521insT) is associated with Nijmegen breakage syndrome (ClinVar).

How common is NBN p.Pro174fs (c.520_521insT) in the general population?

NBN p.Pro174fs (c.520_521insT) is absent from gnomAD (gnomAD).

NBN p.Pro174fs

c.520_521insT · rs2129889298 · VCV1070710

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

Nijmegen breakage syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: NBN
Protein: p.Pro174fs
Coding: c.520_521insT
MANE Select: NM_057091 · reported on NM_002485
dbSNP: rs2129889298
Type: Insertion
Location: chr8:89978283 (GRCh38)
Structure: AlphaFold pLDDT 75.83 · 5 PDB
Residue 174: a disulfide bond

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

Disease context

Nijmegen breakage syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NBN p.Pro174Leu Uncertain significance ★★ ⚠ same residue
NBN p.Pro174Thr Uncertain significance ★★ ⚠ same residue
NBN p.Pro174= Likely benign ★★ same residue
NBN p.Ile597fs Pathogenic/Likely pathogenic ★★ same condition
NBN p.Asn414_Ser415insIle Uncertain significance ★★ same condition
NBN p.Ala241delinsGlyArgAlaArgTrpLeuThrProValIleProAlaLeuTrpGluAlaGluAlaGlyGlySerArgXaaXaaXaaLysLysLysLysLysLysLysArgAsnTer Pathogenic ★ same condition
NBN p.Asp38delinsGluAlaGlyArgGlyGlySerArgLeuTer Pathogenic ★ same condition
NBN p.Asp70fs Pathogenic ★ same condition

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/nbn-p-pro174fs (accessed [today's date]).

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