Is NBN p.Ser40= (c.120G>T) pathogenic?

NBN p.Ser40= (c.120G>T) is classified Conflicting classifications of pathogenicity in NBN (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-01-25). Ultra-rare (popmax 0.0107%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with NBN p.Ser40= (c.120G>T)?

NBN p.Ser40= (c.120G>T) is associated with hereditary neoplastic syndrome, Nijmegen breakage syndrome (ClinVar).

How common is NBN p.Ser40= (c.120G>T) in the general population?

NBN p.Ser40= (c.120G>T) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

NBN p.Ser40=

c.120G>T · rs774989816 · VCV184454

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.8	GERP -5
Overall
CADD	3.742	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0107% African / African-American · 8/74,868 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00093% 15/1,613,744 alleles · ultra-rare exomes 12/1,461,668 · genomes 3/152,076 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,358
Admixed American	0.00667%	14,997
Remaining individualsnot grpmax-eligible	0.0048%	20,823

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.Ser40=
Coding: c.120G>T
MANE Select: NM_002485
dbSNP: rs774989816
Type: single nucleotide variant
Location: chr8:89982773 (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.Ser40Leu Uncertain significance ★★ ⚠ 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
NBN c.172-1G>T Likely pathogenic ★★ same condition
NBN c.172-2A>G Likely pathogenic ★★ same condition
NBN c.1845+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-ser40 (accessed [today's date]).

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