Is NBN p.Pro381fs (c.1142del) pathogenic?

NBN p.Pro381fs (c.1142del) is classified Pathogenic in NBN (ClinVar, Multiple submitters, 16 submitters; last evaluated 2025-11-17). Very rare (popmax 0.0072%, nfe); Associated with Nijmegen breakage syndrome.

What condition is associated with NBN p.Pro381fs (c.1142del)?

NBN p.Pro381fs (c.1142del) is associated with Nijmegen breakage syndrome, acute lymphoblastic leukemia, hereditary neoplastic syndrome (ClinVar).

How common is NBN p.Pro381fs (c.1142del) in the general population?

NBN p.Pro381fs (c.1142del) is very rare (popmax 0.0072%, nfe) (gnomAD).

NBN p.Pro381fs

c.1142del · rs587781969 · VCV141731

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 16 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0072%, nfe)

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 0.13	GERP -3.4, phastCons 0.73
Overall
CADD	33.0	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 0.0072% European (non-Finnish) · 85/1,179,766 alleles

Filtering AF 0.00596% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00549%

Overall 0.00539% 87/1,613,320 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0072%	13,880
Remaining individualsnot grpmax-eligible	0.0032%	31,230

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.Pro381fs
Coding: c.1142del
MANE Select: NM_057091 · reported on NM_002485
dbSNP: rs587781969
Type: Deletion
Location: chr8:89955538 (GRCh38)
Structure: AlphaFold pLDDT 75.83 · 5 PDB

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

Also linked: acute lymphoblastic leukemia hereditary neoplastic syndrome aplastic anemia

Similar variants

NBN p.Pro381= Likely benign ★★ same residue
NBN p.Pro381Thr 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-pro381fs (accessed [today's date]).

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