Is NBN p.Pro694= (c.2082T>G) pathogenic?

NBN p.Pro694= (c.2082T>G) is classified Benign/Likely benign in NBN (ClinVar, Multiple submitters, 18 submitters; last evaluated 2026-02-04). Common (popmax 7.51%, afr) — too common for a highly-penetrant pathogenic allele; Associated with hereditary neoplastic syndrome.

What condition is associated with NBN p.Pro694= (c.2082T>G)?

NBN p.Pro694= (c.2082T>G) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, acute lymphoblastic leukemia (ClinVar).

NBN p.Pro694=

Q: How common is NBN p.Pro694= (c.2082T>G) in the general population?

NBN p.Pro694= (c.2082T>G) is common (popmax 7.51%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2082T>G · rs7823648 · VCV140767

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 18 submitters

gnomAD v4.1

Common

common (popmax 7.51%, afr) — too common for a highly-penetrant pathogenic allele

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 1.5	GERP -0.81, phastCons 1
Overall
CADD	8.242	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.51% African / African-American · 5,603/74,656 alleles

Filtering AF 7.34% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.27%

Overall 0.415% 6,648/1,603,120 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	7.51%	13
Ashkenazi Jewishnot grpmax-eligible	0.569%	176
Remaining individualsnot grpmax-eligible	0.544%	184
Admixed American	0.535%	187
Middle Eastern	0.397%	252
European (non-Finnish)	0.0155%	6,465
South Asian	0.0143%	6,990

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.Pro694=
Coding: c.2082T>G
MANE Select: NM_057091 · reported on NM_002485
dbSNP: rs7823648
Type: single nucleotide variant
Location: chr8:89943355 (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: hereditary breast ovarian cancer syndrome acute lymphoblastic leukemia Nijmegen breakage syndrome

Similar variants

NBN p.Pro694Arg Uncertain significance ★★ ⚠ same residue
NBN p.Pro694Ala Uncertain significance ★ ⚠ same residue
NBN p.Pro694Ser 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

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-pro694 (accessed [today's date]).

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