Is NBN p.Ala8Pro (c.22G>C) pathogenic?

NBN p.Ala8Pro (c.22G>C) is classified Uncertain significance in NBN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-11). AlphaMissense: likely benign (0.14); Absent from gnomAD v4.1; Associated with Nijmegen breakage syndrome.

What condition is associated with NBN p.Ala8Pro (c.22G>C)?

NBN p.Ala8Pro (c.22G>C) is associated with Nijmegen breakage syndrome (ClinVar).

How common is NBN p.Ala8Pro (c.22G>C) in the general population?

NBN p.Ala8Pro (c.22G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NBN p.Ala8Pro (c.22G>C)?

AlphaMissense predicts likely benign (score 0.14) — an in-silico prediction, not a clinical call.

NBN p.Ala8Pro

c.22G>C · rs2129938188 · VCV2708905

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.14 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Nijmegen breakage syndrome

Computational evidence

Protein change
AlphaMissense	0.14	likely benign
REVEL	0.153	moderately benign-leaning
SaProt	LLR -7.08	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 0.17	GERP 1.1
Overall
CADD	17.46	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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.Ala8Pro
Coding: c.22G>C
MANE Select: NM_057091 · reported on NM_002485
dbSNP: rs2129938188
Type: single nucleotide variant
Location: chr8:89984540 (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

Similar variants

NBN p.Ala8Thr Uncertain significance ★★ ⚠ same residue
NBN p.Ala8Val Uncertain significance ★★ ⚠ same residue
NBN p.Ala8Gly Uncertain significance ★ ⚠ same residue
NBN p.Ala8= Likely benign ★ 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-ala8pro (accessed [today's date]).

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