Is NBN p.Ile703Ser (c.2108T>G) pathogenic?

NBN p.Ile703Ser (c.2108T>G) is classified Uncertain significance in NBN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-03). AlphaMissense: likely pathogenic (0.9273); Absent from gnomAD v4.1; Associated with Nijmegen breakage syndrome.

What condition is associated with NBN p.Ile703Ser (c.2108T>G)?

NBN p.Ile703Ser (c.2108T>G) is associated with Nijmegen breakage syndrome (ClinVar).

How common is NBN p.Ile703Ser (c.2108T>G) in the general population?

NBN p.Ile703Ser (c.2108T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NBN p.Ile703Ser (c.2108T>G)?

AlphaMissense predicts likely pathogenic (score 0.9273) — an in-silico prediction, not a clinical call.

NBN p.Ile703Ser

c.2108T>G · rs1554555819 · VCV2106474

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9273 · 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	0.9273	likely pathogenic · top 10% in NBN
REVEL	0.872	moderately pathogenic-leaning
SaProt	LLR -5.17	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 11	GERP 1.8, phastCons 1
Overall
CADD	24.4	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.Ile703Ser
Coding: c.2108T>G
MANE Select: NM_057091 · reported on NM_002485
dbSNP: rs1554555819
Type: single nucleotide variant
Location: chr8:89943329 (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.Ile703Thr Uncertain significance ★★ ⚠ same residue
NBN p.Ile703Val Uncertain significance ★★ ⚠ same residue
NBN p.Ile703Phe Uncertain significance ★ ⚠ same residue
NBN p.Ile703= 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-ile703ser (accessed [today's date]).

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