Is NBN p.Pro199Ser (c.595C>T) pathogenic?

NBN p.Pro199Ser (c.595C>T) is classified Conflicting classifications of pathogenicity in NBN (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2024-12-29). AlphaMissense: likely benign (0.1188); Very rare (popmax 0.00178%, nfe); Associated with Nijmegen breakage syndrome.

What condition is associated with NBN p.Pro199Ser (c.595C>T)?

NBN p.Pro199Ser (c.595C>T) is associated with Nijmegen breakage syndrome, acute lymphoblastic leukemia, hereditary neoplastic syndrome (ClinVar).

How common is NBN p.Pro199Ser (c.595C>T) in the general population?

NBN p.Pro199Ser (c.595C>T) is very rare (popmax 0.00178%, nfe) (gnomAD).

What do computational predictors say about NBN p.Pro199Ser (c.595C>T)?

AlphaMissense predicts likely benign (score 0.1188) — an in-silico prediction, not a clinical call.

NBN p.Pro199Ser

c.595C>T · rs587780097 · VCV127874

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.1188 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00178%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Nijmegen breakage syndrome

Computational evidence

Protein change
AlphaMissense	0.1188	likely benign
REVEL	0.181	moderately benign-leaning
SaProt	LLR -8.81	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 8.5	GERP 0.94, phastCons 1
Overall
CADD	23.4	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 0.00178% European (non-Finnish) · 21/1,178,784 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000972%

Overall 0.00199% 32/1,611,754 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0305%	3,283
European (non-Finnish)grpmax	0.00178%	56,132
Remaining individualsnot grpmax-eligible	0.0016%	62,350
South Asian	0.0011%	90,972

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro199Ser
Coding: c.595C>T
MANE Select: NM_057091 · reported on NM_002485
dbSNP: rs587780097
Type: single nucleotide variant
Location: chr8:89971280 (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

Nijmegen breakage syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: acute lymphoblastic leukemia hereditary neoplastic syndrome aplastic anemia

Similar variants

NBN p.Pro199Ala Uncertain significance ★ ⚠ same residue
NBN p.Pro199Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
NBN p.Pro199Leu Uncertain significance ★ ⚠ 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-pro199ser (accessed [today's date]).

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