Is NBN p.Ala249= (c.747T>A) pathogenic?

NBN p.Ala249= (c.747T>A) is classified Likely benign in NBN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-11-18). Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with NBN p.Ala249= (c.747T>A)?

NBN p.Ala249= (c.747T>A) is associated with hereditary neoplastic syndrome, Nijmegen breakage syndrome (ClinVar).

How common is NBN p.Ala249= (c.747T>A) in the general population?

NBN p.Ala249= (c.747T>A) is absent from gnomAD v4.1 (gnomAD).

NBN p.Ala249=

c.747T>A · rs780134747 · VCV461579

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

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 0.78	GERP -3.5, phastCons 0.98
Overall
CADD	7.102	PHRED · no single calibrated threshold — expert panels disagree

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.Ala249=
Coding: c.747T>A
MANE Select: NM_057091 · reported on NM_002485
dbSNP: rs780134747
Type: single nucleotide variant
Location: chr8:89970513 (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.Ala249Asp Uncertain significance ★★ ⚠ same residue
NBN p.Ala249Pro Uncertain significance ★ ⚠ same residue
NBN p.Ala249Thr 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-ala249 (accessed [today's date]).

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