Is NBN p.Ile703Val (c.2107A>G) pathogenic?

NBN p.Ile703Val (c.2107A>G) is classified Uncertain significance in NBN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-08). AlphaMissense: likely benign (0.3052); Very rare (popmax 0.00133%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with NBN p.Ile703Val (c.2107A>G)?

NBN p.Ile703Val (c.2107A>G) is associated with hereditary neoplastic syndrome, Nijmegen breakage syndrome (ClinVar).

How common is NBN p.Ile703Val (c.2107A>G) in the general population?

NBN p.Ile703Val (c.2107A>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about NBN p.Ile703Val (c.2107A>G)?

AlphaMissense predicts likely benign (score 0.3052) — an in-silico prediction, not a clinical call.

NBN p.Ile703Val

c.2107A>G · rs942302974 · VCV1410814

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3052 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3052	likely benign
REVEL	0.476	indeterminate
SaProt	LLR -5.80	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.8, phastCons 1
Overall
CADD	23.2	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

Grpmax group 0.00133% African / African-American · 1/74,968 alleles

Overall 6.85e-05% 1/1,458,870 alleles · very rare

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.Ile703Val
Coding: c.2107A>G
MANE Select: NM_057091 · reported on NM_002485
dbSNP: rs942302974
Type: single nucleotide variant
Location: chr8:89943330 (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.Ile703Thr Uncertain significance ★★ ⚠ same residue
NBN p.Ile703Phe Uncertain significance ★ ⚠ same residue
NBN p.Ile703Ser 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-ile703val (accessed [today's date]).

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