Is NBN p.Glu552fs (c.1654dup) pathogenic?

NBN p.Glu552fs (c.1654dup) is classified Pathogenic/Likely pathogenic in NBN (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-14). Very rare (popmax 0.00133%, afr); Associated with aplastic anemia.

What condition is associated with NBN p.Glu552fs (c.1654dup)?

NBN p.Glu552fs (c.1654dup) is associated with aplastic anemia, Nijmegen breakage syndrome, hereditary neoplastic syndrome (ClinVar).

How common is NBN p.Glu552fs (c.1654dup) in the general population?

NBN p.Glu552fs (c.1654dup) is very rare (popmax 0.00133%, afr) (gnomAD).

NBN p.Glu552fs

c.1654dup · rs760237820 · VCV530754

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 0.00133%, afr)

Conditions

aplastic anemia

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 3.4	GERP 0.56, phastCons 1
Overall
CADD	23.4	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 0.00133% African / African-American · 1/75,038 alleles

Overall 0.000657% 1/152,248 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.Glu552fs
Coding: c.1654dup
MANE Select: NM_057091 · reported on NM_002485
dbSNP: rs760237820
Type: Duplication
Location: chr8:89953434 (GRCh38)
Structure: AlphaFold pLDDT 75.83 · 5 PDB

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

Disease context

aplastic anemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Nijmegen breakage syndrome hereditary neoplastic syndrome

Similar variants

NBN p.Glu552Gln Uncertain significance ★★ ⚠ same residue
NBN p.Arg107fs Pathogenic ★★ same condition
NBN p.Arg445Ter Pathogenic ★★ same condition
NBN p.Arg466fs Pathogenic/Likely pathogenic ★★ same condition
NBN p.Cys478fs Pathogenic ★★ same condition
NBN p.Gln344fs Likely pathogenic ★★ same condition
NBN p.Gln460fs Pathogenic/Likely pathogenic ★★ same condition
NBN p.Glu248fs Pathogenic/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-glu552fs (accessed [today's date]).

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