Is NBN p.Pro283Ser (c.847C>T) pathogenic?

NBN p.Pro283Ser (c.847C>T) is classified Uncertain significance in NBN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-08-01). AlphaMissense: likely benign (0.0711); Very rare (popmax 0.00669%, eas); Associated with Nijmegen breakage syndrome.

What condition is associated with NBN p.Pro283Ser (c.847C>T)?

NBN p.Pro283Ser (c.847C>T) is associated with Nijmegen breakage syndrome, hereditary neoplastic syndrome (ClinVar).

How common is NBN p.Pro283Ser (c.847C>T) in the general population?

NBN p.Pro283Ser (c.847C>T) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about NBN p.Pro283Ser (c.847C>T)?

AlphaMissense predicts likely benign (score 0.0711) — an in-silico prediction, not a clinical call.

NBN p.Pro283Ser

c.847C>T · rs1811453358 · VCV953831

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0711 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Nijmegen breakage syndrome

Computational evidence

Protein change
AlphaMissense	0.0711	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -3.23	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 1	GERP 0.79, phastCons 1
Overall
CADD	9.961	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 0.00669% East Asian · 3/44,860 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000892%

Overall 0.000186% 3/1,613,898 alleles · very rare exomes 3/1,461,656 · genomes 0/152,242 · joint denominator

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.Pro283Ser
Coding: c.847C>T
MANE Select: NM_002485
dbSNP: rs1811453358
Type: single nucleotide variant
Location: chr8:89970413 (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

Also linked: hereditary neoplastic syndrome

Similar variants

NBN p.Pro283Arg Uncertain significance ★★ ⚠ same residue
NBN p.Pro283His Uncertain significance ★★ ⚠ same residue
NBN p.Pro283Leu Uncertain significance ★ ⚠ same residue
NBN p.Pro283= Likely benign ★ same residue
NBN p.Pro283fs Pathogenic/Likely pathogenic ★★ 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

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-pro283ser (accessed [today's date]).

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