Is NBN p.Ser486Pro (c.1456T>C) pathogenic?

NBN p.Ser486Pro (c.1456T>C) is classified Uncertain significance in NBN (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-11-10). AlphaMissense: likely benign (0.085); Very rare (popmax 0.000763%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with NBN p.Ser486Pro (c.1456T>C)?

NBN p.Ser486Pro (c.1456T>C) is associated with hereditary neoplastic syndrome, Nijmegen breakage syndrome, aplastic anemia (ClinVar).

How common is NBN p.Ser486Pro (c.1456T>C) in the general population?

NBN p.Ser486Pro (c.1456T>C) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about NBN p.Ser486Pro (c.1456T>C)?

AlphaMissense predicts likely benign (score 0.085) — an in-silico prediction, not a clinical call.

NBN p.Ser486Pro

c.1456T>C · rs587781380 · VCV140934

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.085 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.085	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	LLR -7.14	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.23	acceptor loss, 16 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 5.9	GERP 1.8, phastCons 1
Overall
CADD	21.1	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 0.000763% European (non-Finnish) · 9/1,179,362 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000682% 11/1,612,936 alleles · very rare exomes 11/1,460,704 · genomes 0/152,232 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,460
Finnishnot grpmax-eligible	0.00157%	63,730
European (non-Finnish)grpmax	0.000763%	131,040

Remaining individuals 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.Ser486Pro
Coding: c.1456T>C
MANE Select: NM_002485
dbSNP: rs587781380
Type: single nucleotide variant
Location: chr8:89953633 (GRCh38)
Structure: AlphaFold pLDDT 75.83 · 5 PDB

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 aplastic anemia

Similar variants

NBN p.Ser486Phe Uncertain significance ★★ ⚠ same residue
NBN p.Ser486Thr Uncertain significance ★★ ⚠ same residue
NBN p.Ser486Cys Uncertain significance ★ ⚠ same residue
NBN p.Ser486= 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-ser486pro (accessed [today's date]).

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