Is NBN p.Ser667Pro (c.1999T>C) pathogenic?

NBN p.Ser667Pro (c.1999T>C) is classified Conflicting classifications of pathogenicity in NBN (ClinVar, Conflicting submitters, 14 submitters; last evaluated 2025-07-13). AlphaMissense: likely benign (0.0751); Ultra-rare (popmax 0.05%, amr); Associated with Nijmegen breakage syndrome.

What condition is associated with NBN p.Ser667Pro (c.1999T>C)?

NBN p.Ser667Pro (c.1999T>C) is associated with Nijmegen breakage syndrome, hereditary breast ovarian cancer syndrome, acute lymphoblastic leukemia (ClinVar).

How common is NBN p.Ser667Pro (c.1999T>C) in the general population?

NBN p.Ser667Pro (c.1999T>C) is ultra-rare (popmax 0.05%, amr) (gnomAD).

What do computational predictors say about NBN p.Ser667Pro (c.1999T>C)?

AlphaMissense predicts likely benign (score 0.0751) — an in-silico prediction, not a clinical call.

NBN p.Ser667Pro

c.1999T>C · rs587780091 · VCV127863

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 14 submitters

AlphaMissense

likely benign

0.0751 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.05%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Nijmegen breakage syndrome

Computational evidence

Protein change
AlphaMissense	0.0751	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -6.14	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.29	GERP -3.8, phastCons 0.42
Overall
CADD	6.808	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.05% Admixed American · 30/59,964 alleles

Filtering AF 0.036% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0312%

Overall 0.00988% 158/1,599,276 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.05%	1,999
Remaining individualsnot grpmax-eligible	0.0129%	7,746
European (non-Finnish)	0.01%	9,975
African / African-American	0.00402%	24,875

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.Ser667Pro
Coding: c.1999T>C
MANE Select: NM_057091 · reported on NM_002485
dbSNP: rs587780091
Type: single nucleotide variant
Location: chr8:89946211 (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: hereditary breast ovarian cancer syndrome acute lymphoblastic leukemia hereditary neoplastic syndrome aplastic anemia

Similar variants

NBN p.Ser667= Likely benign ★★ same residue
NBN p.Ser667Phe Uncertain significance ★ ⚠ same residue
NBN p.Ser667fs Pathogenic ★ 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

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-ser667pro (accessed [today's date]).

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