Is NBN p.Pro340Ser (c.1018C>T) pathogenic?

NBN p.Pro340Ser (c.1018C>T) is classified Uncertain significance in NBN (ClinVar, Single submitter, 1 submitter; last evaluated 2020-09-30). AlphaMissense: likely benign (0.0944); Very rare (popmax 0.00133%, afr); Associated with Nijmegen breakage syndrome.

What condition is associated with NBN p.Pro340Ser (c.1018C>T)?

NBN p.Pro340Ser (c.1018C>T) is associated with Nijmegen breakage syndrome (ClinVar).

How common is NBN p.Pro340Ser (c.1018C>T) in the general population?

NBN p.Pro340Ser (c.1018C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about NBN p.Pro340Ser (c.1018C>T)?

AlphaMissense predicts likely benign (score 0.0944) — an in-silico prediction, not a clinical call.

NBN p.Pro340Ser

c.1018C>T · rs1586066127 · VCV1060128

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0944 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Nijmegen breakage syndrome

Computational evidence

Protein change
AlphaMissense	0.0944	likely benign
REVEL	0.025	moderately benign-leaning
SaProt	LLR -5.57	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 4.6	GERP 1.1, phastCons 1
Overall
CADD	19.04	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 · 1/75,034 alleles

Overall 6.2e-05% 1/1,613,806 alleles · very rare exomes 1/1,461,514 · genomes 0/152,292 · 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.Pro340Ser
Coding: c.1018C>T
MANE Select: NM_002485
dbSNP: rs1586066127
Type: single nucleotide variant
Location: chr8:89958831 (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.Pro340Thr Uncertain significance ★★ ⚠ same residue
NBN p.Pro340= Likely benign ★★ same residue
NBN p.Pro340Ala 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-pro340ser (accessed [today's date]).

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