Is NBN p.Ser207= (c.621T>C) pathogenic?

NBN p.Ser207= (c.621T>C) is classified Conflicting classifications of pathogenicity in NBN (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-01). Very rare (popmax 0.00167%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with NBN p.Ser207= (c.621T>C)?

NBN p.Ser207= (c.621T>C) is associated with hereditary neoplastic syndrome, Nijmegen breakage syndrome (ClinVar).

How common is NBN p.Ser207= (c.621T>C) in the general population?

NBN p.Ser207= (c.621T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

NBN p.Ser207=

c.621T>C · rs876658177 · VCV229759

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 0.56, phastCons 1
Overall
CADD	11.25	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,978 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000434% 7/1,613,100 alleles · very rare exomes 5/1,460,912 · genomes 2/152,188 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,978
African / African-American	0.00134%	74,876
European (non-Finnish)	0.000424%	235,899

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.Ser207=
Coding: c.621T>C
MANE Select: NM_002485
dbSNP: rs876658177
Type: single nucleotide variant
Location: chr8:89971254 (GRCh38)
Structure: AlphaFold pLDDT 75.83 · 5 PDB
Residue 207: 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

Similar variants

NBN p.Ser207Ile Uncertain significance ★★ ⚠ same residue
NBN p.Ser207Gly Uncertain significance ★ ⚠ same residue
NBN p.Ser207Thr Uncertain significance ★ ⚠ same residue
NBN p.Ser207Asn 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-ser207 (accessed [today's date]).

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