Is NBN p.Arg468Ser (c.1404G>C) pathogenic?

NBN p.Arg468Ser (c.1404G>C) is classified Uncertain significance in NBN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-12). AlphaMissense: likely pathogenic (0.7459); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with NBN p.Arg468Ser (c.1404G>C)?

NBN p.Arg468Ser (c.1404G>C) is associated with hereditary neoplastic syndrome, Nijmegen breakage syndrome (ClinVar).

How common is NBN p.Arg468Ser (c.1404G>C) in the general population?

NBN p.Arg468Ser (c.1404G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NBN p.Arg468Ser (c.1404G>C)?

AlphaMissense predicts likely pathogenic (score 0.7459) — an in-silico prediction, not a clinical call.

NBN p.Arg468Ser

c.1404G>C · rs730881851 · VCV1482756

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7459 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.7459	likely pathogenic
REVEL	0.208	benign-leaning
SaProt	LLR -8.20	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.092	GERP -1, phastCons 0.55
Overall
CADD	18.22	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.Arg468Ser
Coding: c.1404G>C
MANE Select: NM_057091 · reported on NM_002485
dbSNP: rs730881851
Type: single nucleotide variant
Location: chr8:89953685 (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.Arg468Gly Uncertain significance ★★ ⚠ same residue
NBN p.Arg468Lys Uncertain significance ★★ ⚠ same residue
NBN p.Arg468Thr 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-arg468ser (accessed [today's date]).

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