Is NBN p.Arg299Lys (c.896G>A) pathogenic?

NBN p.Arg299Lys (c.896G>A) is classified Uncertain significance in NBN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-03). AlphaMissense: likely benign (0.117); Very rare (popmax 0.0022%, sas); Associated with aplastic anemia.

What condition is associated with NBN p.Arg299Lys (c.896G>A)?

NBN p.Arg299Lys (c.896G>A) is associated with aplastic anemia, Nijmegen breakage syndrome, hereditary neoplastic syndrome (ClinVar).

How common is NBN p.Arg299Lys (c.896G>A) in the general population?

NBN p.Arg299Lys (c.896G>A) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about NBN p.Arg299Lys (c.896G>A)?

AlphaMissense predicts likely benign (score 0.117) — an in-silico prediction, not a clinical call.

NBN p.Arg299Lys

c.896G>A · rs754113612 · VCV1765281

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.117 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

aplastic anemia

Computational evidence

Protein change
AlphaMissense	0.117	likely benign
REVEL	0.101	moderately benign-leaning
SaProt	LLR -4.75	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.95	donor loss at this position · masked 0 · deltas
Pangolin	Δ0.60	loss · gain 0.04 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, phastCons 1
Overall
CADD	25.4	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 0.0022% South Asian · 2/90,870 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000206% 3/1,453,320 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,435
Remaining individualsnot grpmax-eligible	0.00161%	62,240

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.Arg299Lys
Coding: c.896G>A
MANE Select: NM_057091 · reported on NM_002485
dbSNP: rs754113612
Type: single nucleotide variant
Location: chr8:89970364 (GRCh38)
Structure: AlphaFold pLDDT 75.83 · 5 PDB

Full NBN gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

aplastic anemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Nijmegen breakage syndrome hereditary neoplastic syndrome

Similar variants

NBN p.Arg299= Uncertain significance ★★ same residue
NBN p.Arg299Ser Uncertain significance ★★ ⚠ same residue
NBN p.Arg299Thr 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-arg299lys (accessed [today's date]).

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