Is NBN p.Arg43Ter (c.127C>T) pathogenic?

NBN p.Arg43Ter (c.127C>T) is classified Conflicting classifications of pathogenicity in NBN (ClinVar, Conflicting submitters, 16 submitters; last evaluated 2025-11-10). Very rare (popmax 0.00668%, afr); Associated with NBN-related disorder.

What condition is associated with NBN p.Arg43Ter (c.127C>T)?

NBN p.Arg43Ter (c.127C>T) is associated with NBN-related disorder, gastric cancer, acute lymphoblastic leukemia (ClinVar).

How common is NBN p.Arg43Ter (c.127C>T) in the general population?

NBN p.Arg43Ter (c.127C>T) is very rare (popmax 0.00668%, afr) (gnomAD).

NBN p.Arg43Ter

c.127C>T · rs200287925 · VCV142203

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 16 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00668%, afr)

Conditions

NBN-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP -3.2, phastCons 1
Overall
CADD	38.0	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 0.00668% African / African-American · 5/74,858 alleles

Filtering AF 0.00326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00294%

Overall 0.00415% 67/1,613,736 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0172%	5,818
African / African-Americangrpmax	0.00668%	14,972
European (non-Finnish)	0.00424%	23,598
South Asian	0.0011%	91,080

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg43Ter
Coding: c.127C>T
MANE Select: NM_057091 · reported on NM_002485
dbSNP: rs200287925
Type: single nucleotide variant
Location: chr8:89982766 (GRCh38)
Structure: AlphaFold pLDDT 75.83 · 5 PDB
Residue 43: the 'disordered' region

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

Disease context

NBN-related disorder

Also linked: gastric cancer acute lymphoblastic leukemia Nijmegen breakage syndrome hereditary neoplastic syndrome aplastic anemia

Similar variants

NBN p.Arg43Gln Uncertain significance ★★ ⚠ same residue
NBN p.Arg43Leu Uncertain significance ★★ ⚠ same residue
NBN p.Arg43Gly Uncertain significance ★ ⚠ same residue
NBN p.Arg43= Likely benign ★ same residue
NBN c.1124+1G>C Likely pathogenic ★★ same condition
NBN c.1124+2T>G Likely pathogenic ★★ same condition
NBN c.1397+2T>A Likely pathogenic ★★ same condition
NBN c.171+1G>A 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-arg43ter (accessed [today's date]).

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