Is NBN p.Asp707Glu (c.2121T>A) pathogenic?

NBN p.Asp707Glu (c.2121T>A) is classified Uncertain significance in NBN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-01). AlphaMissense: likely pathogenic (0.9267); Absent from gnomAD v4.1; Associated with Nijmegen breakage syndrome.

What condition is associated with NBN p.Asp707Glu (c.2121T>A)?

NBN p.Asp707Glu (c.2121T>A) is associated with Nijmegen breakage syndrome, hereditary neoplastic syndrome (ClinVar).

How common is NBN p.Asp707Glu (c.2121T>A) in the general population?

NBN p.Asp707Glu (c.2121T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NBN p.Asp707Glu (c.2121T>A)?

AlphaMissense predicts likely pathogenic (score 0.9267) — an in-silico prediction, not a clinical call.

NBN p.Asp707Glu

c.2121T>A · rs2488191442 · VCV1976561

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9267 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Nijmegen breakage syndrome

Computational evidence

Protein change
AlphaMissense	0.9267	likely pathogenic · top 10% in NBN
REVEL	0.712	pathogenic-leaning
SaProt	LLR -6.28	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.72	GERP -0.68, phastCons 0.96
Overall
CADD	18.73	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NBN
Protein: p.Asp707Glu
Coding: c.2121T>A
MANE Select: NM_057091 · reported on NM_002485
dbSNP: rs2488191442
Type: single nucleotide variant
Location: chr8:89943316 (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 neoplastic syndrome

Similar variants

NBN p.Asp707Asn Uncertain significance ★ ⚠ same residue
NBN p.Asp707His Uncertain significance ★ ⚠ same residue
NBN p.Asp707_Ile709del Uncertain significance ★★ same residue
NBN p.Asp707fs Likely 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

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-asp707glu (accessed [today's date]).

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