Is NBN p.Pro199Arg (c.596C>G) pathogenic?

NBN p.Pro199Arg (c.596C>G) is classified Conflicting classifications of pathogenicity in NBN (ClinVar, Conflicting submitters, 14 submitters; last evaluated 2026-02-20). AlphaMissense: likely benign (0.1524); Very rare (popmax 0.00161%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with NBN p.Pro199Arg (c.596C>G)?

NBN p.Pro199Arg (c.596C>G) is associated with hereditary neoplastic syndrome, Nijmegen breakage syndrome, aplastic anemia (ClinVar).

How common is NBN p.Pro199Arg (c.596C>G) in the general population?

NBN p.Pro199Arg (c.596C>G) is very rare (popmax 0.00161%, nfe) (gnomAD).

What do computational predictors say about NBN p.Pro199Arg (c.596C>G)?

AlphaMissense predicts likely benign (score 0.1524) — an in-silico prediction, not a clinical call.

NBN p.Pro199Arg

c.596C>G · rs730881844 · VCV182713

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 14 submitters

AlphaMissense

likely benign

0.1524 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1524	likely benign
REVEL	0.405	indeterminate
SaProt	LLR -11.49	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	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

Grpmax group 0.00161% European (non-Finnish) · 19/1,178,840 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000831%

Overall 0.00124% 20/1,611,842 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00161%	62,044
African / African-American	0.00134%	74,824

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.Pro199Arg
Coding: c.596C>G
MANE Select: NM_057091 · reported on NM_002485
dbSNP: rs730881844
Type: single nucleotide variant
Location: chr8:89971279 (GRCh38)
Structure: AlphaFold pLDDT 75.83 · 5 PDB
Residue 199: a disulfide bond; a β-strand

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 aplastic anemia

Similar variants

NBN p.Pro199Ala Uncertain significance ★ ⚠ same residue
NBN p.Pro199Leu Uncertain significance ★ ⚠ same residue
NBN p.Pro199Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
NBN p.Pro199= 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-pro199arg (accessed [today's date]).

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