Is NBN p.Asp211Glu (c.633T>A) pathogenic?

NBN p.Asp211Glu (c.633T>A) is classified Uncertain significance in NBN (ClinVar, Multiple submitters, 14 submitters; last evaluated 2025-04-01). AlphaMissense: likely pathogenic (0.6215); Very rare (popmax 0.00297%, nfe); Associated with diffuse midline glioma, H3 K27-altered.

What condition is associated with NBN p.Asp211Glu (c.633T>A)?

NBN p.Asp211Glu (c.633T>A) is associated with diffuse midline glioma, H3 K27-altered, Nijmegen breakage syndrome, hereditary neoplastic syndrome (ClinVar).

How common is NBN p.Asp211Glu (c.633T>A) in the general population?

NBN p.Asp211Glu (c.633T>A) is very rare (popmax 0.00297%, nfe) (gnomAD).

What do computational predictors say about NBN p.Asp211Glu (c.633T>A)?

AlphaMissense predicts likely pathogenic (score 0.6215) — an in-silico prediction, not a clinical call.

NBN p.Asp211Glu

c.633T>A · rs377700348 · VCV140805

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

AlphaMissense

likely pathogenic

0.6215 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00297%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

diffuse midline glioma, H3 K27-altered

Computational evidence

Protein change
AlphaMissense	0.6215	likely pathogenic
REVEL	0.247	benign-leaning
SaProt	LLR -10.18	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.3	GERP -2.2, phastCons 1
Overall
CADD	20.3	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 0.00297% European (non-Finnish) · 35/1,179,552 alleles

Filtering AF 0.00215% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00191%

Overall 0.00229% 37/1,613,212 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,570
European (non-Finnish)grpmax	0.00297%	33,701
Admixed American	0.00167%	59,968

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.Asp211Glu
Coding: c.633T>A
MANE Select: NM_057091 · reported on NM_002485
dbSNP: rs377700348
Type: single nucleotide variant
Location: chr8:89971242 (GRCh38)
Structure: AlphaFold pLDDT 75.83 · 5 PDB
Residue 211: a disulfide bond; a β-strand

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

Disease context

diffuse midline glioma, H3 K27-altered — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Nijmegen breakage syndrome hereditary neoplastic syndrome aplastic anemia

For Diffuse intrinsic pontine glioma (Orphanet):

Onset: All ages
Prevalence: <1 / 1 000 000 (Netherlands)

Similar variants

NBN p.Asp211His Uncertain significance ★★ ⚠ same residue
NBN p.Asp211= Likely benign ★★ same residue
NBN p.Asp211Ala Uncertain significance ★ ⚠ same residue
NBN p.Asp211Asn 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

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-asp211glu (accessed [today's date]).

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