Is NBN p.Ser72Phe (c.215C>T) pathogenic?

NBN p.Ser72Phe (c.215C>T) is classified Uncertain significance in NBN (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-01-15). AlphaMissense: likely pathogenic (0.9913); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with NBN p.Ser72Phe (c.215C>T)?

NBN p.Ser72Phe (c.215C>T) is associated with hereditary neoplastic syndrome, Nijmegen breakage syndrome (ClinVar).

How common is NBN p.Ser72Phe (c.215C>T) in the general population?

NBN p.Ser72Phe (c.215C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NBN p.Ser72Phe (c.215C>T)?

AlphaMissense predicts likely pathogenic (score 0.9913) — an in-silico prediction, not a clinical call.

NBN p.Ser72Phe

c.215C>T · rs1060503484 · VCV411781

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9913 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9913	likely pathogenic · top 1% in NBN
REVEL	0.866	moderately pathogenic-leaning
SaProt	LLR -16.03	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.33 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Overall
CADD	29.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NBN
Protein: p.Ser72Phe
Coding: c.215C>T
MANE Select: NM_057091 · reported on NM_002485
dbSNP: rs1060503484
Type: single nucleotide variant
Location: chr8:89981480 (GRCh38)
Structure: AlphaFold pLDDT 75.83 · 5 PDB
Residue 72: the 'disordered' region

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.Ser72= Likely benign ★ same residue
NBN p.Ser72del Uncertain significance ★ same residue
NBN p.Ser72delinsTrpAsnArgSerGlyGlnPro Uncertain significance same residue
ARTN p.Arg72His Uncertain significance ★ ⚠ same residue
NBN p.Ser72Thr 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

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-ser72phe (accessed [today's date]).

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