Is NBN p.Leu165Phe (c.493C>T) pathogenic?

NBN p.Leu165Phe (c.493C>T) is classified Uncertain significance in NBN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-01). AlphaMissense: likely pathogenic (0.641); Very rare (popmax 0.00111%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with NBN p.Leu165Phe (c.493C>T)?

NBN p.Leu165Phe (c.493C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is NBN p.Leu165Phe (c.493C>T) in the general population?

NBN p.Leu165Phe (c.493C>T) is very rare (popmax 0.00111%, sas) (gnomAD).

What do computational predictors say about NBN p.Leu165Phe (c.493C>T)?

AlphaMissense predicts likely pathogenic (score 0.641) — an in-silico prediction, not a clinical call.

NBN p.Leu165Phe

c.493C>T · VCV3917588

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.641 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00111%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.641	likely pathogenic
REVEL	0.458	indeterminate
SaProt	LLR -11.56	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1.9, phastCons 1
Overall
CADD	24.7	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

Grpmax group 0.00111% South Asian · 1/90,466 alleles

Overall 6.97e-05% 1/1,434,494 alleles · very rare

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.Leu165Phe
Coding: c.493C>T
MANE Select: NM_057091 · reported on NM_002485
Type: single nucleotide variant
Location: chr8:89978311 (GRCh38)
Structure: AlphaFold pLDDT 75.83 · 5 PDB
Residue 165: a disulfide bond; an α-helix

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

Similar variants

NBN p.Leu165Ile Uncertain significance ★★ ⚠ same residue
NBN p.Leu165= Likely benign ★★ same residue
NBN p.Leu165fs Pathogenic ★★ same residue
NBN p.Leu165Arg Uncertain significance ★ ⚠ same residue
NBN c.1124+1G>C Likely pathogenic ★★ same condition
NBN c.171+1G>A Likely pathogenic ★★ same condition
NBN c.172-2A>G Likely pathogenic ★★ same condition
NBN c.1845+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-leu165phe (accessed [today's date]).

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