Is NBN p.Arg28fs (c.83_89del) pathogenic?

NBN p.Arg28fs (c.8389del) is classified Pathogenic/Likely pathogenic in NBN (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-07). Very rare (popmax 0.00134%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with NBN p.Arg28fs (c.83_89del)?

NBN p.Arg28fs (c.83_89del) is associated with hereditary neoplastic syndrome, Nijmegen breakage syndrome (ClinVar).

How common is NBN p.Arg28fs (c.83_89del) in the general population?

NBN p.Arg28fs (c.83_89del) is very rare (popmax 0.00134%, afr) (gnomAD).

NBN p.Arg28fs

c.83_89del · rs1554569106 · VCV483951

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

hereditary neoplastic 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 2.9	GERP -0.34, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,890 alleles

Overall 0.000657% 1/152,130 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: NBN
Protein: p.Arg28fs
Coding: c.83_89del
MANE Select: NM_057091 · reported on NM_002485
dbSNP: rs1554569106
Type: Deletion
Location: chr8:89982804 (GRCh38)
Structure: AlphaFold pLDDT 75.83 · 5 PDB

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

Disease context

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

Also linked: Nijmegen breakage syndrome

Similar variants

NBN p.Arg28Gly Uncertain significance ★★ ⚠ same residue
NBN p.Arg28Lys Uncertain significance ★★ ⚠ same residue
NBN c.1397+1_1397+9del Likely pathogenic ★★ same condition
NBN c.1397+1del Pathogenic ★★ same condition
NBN c.163_171+3del Pathogenic/Likely pathogenic ★★ same condition
NBN c.2070+2del Likely pathogenic ★★ same condition
NBN c.2071del Pathogenic/Likely pathogenic ★★ same condition
NBN c.2226_2234+4del Likely 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-arg28fs (accessed [today's date]).

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