Is NPRL2 p.Phe87Ser (c.260T>C) pathogenic?

NPRL2 p.Phe87Ser (c.260T>C) is classified Uncertain significance in NPRL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-24). AlphaMissense: likely pathogenic (0.9936); Very rare (popmax 8.47e-05%, nfe); Associated with epilepsy, familial focal, with variable foci 2.

What condition is associated with NPRL2 p.Phe87Ser (c.260T>C)?

NPRL2 p.Phe87Ser (c.260T>C) is associated with epilepsy, familial focal, with variable foci 2 (ClinVar).

How common is NPRL2 p.Phe87Ser (c.260T>C) in the general population?

NPRL2 p.Phe87Ser (c.260T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Familial focal epilepsy with variable foci inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about NPRL2 p.Phe87Ser (c.260T>C)?

AlphaMissense predicts likely pathogenic (score 0.9936) — an in-silico prediction, not a clinical call.

NPRL2 p.Phe87Ser

c.260T>C · rs2470937915 · VCV2442080

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9936 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

epilepsy, familial focal, with variable foci 2

Computational evidence

Protein change
AlphaMissense	0.9936	likely pathogenic · top 7% in NPRL2
REVEL	0.751	pathogenic-leaning
SaProt	LLR -15.60	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.6, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 3,043 bp · p 1e-06 · regional, not allelic
Overall
CADD	32.0	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 8.47e-05% European (non-Finnish) · 1/1,179,988 alleles

Overall 6.2e-05% 1/1,613,940 alleles · very rare exomes 1/1,461,698 · genomes 0/152,242 · joint denominator

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: NPRL2
Protein: p.Phe87Ser
Coding: c.260T>C
MANE Select: NM_006545
dbSNP: rs2470937915
Type: single nucleotide variant
Location: chr3:50349744 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI 0.58 (gnomAD)
Structure: AlphaFold pLDDT 69.38 · 10 PDB
Residue 87: the 'interaction with pdpk1' region; a β-strand

Full NPRL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

epilepsy, familial focal, with variable foci 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial focal epilepsy with variable foci (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood, Infancy

Similar variants

NPR2 p.Arg989Leu Pathogenic/Likely pathogenic ★★ same condition
NPRL2 c.932+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPRL2 p.Arg295Ter Pathogenic/Likely pathogenic ★★ same condition
NPRL2 p.Glu72Ter Pathogenic/Likely pathogenic ★★ same condition
NPRL2 p.Arg221Cys Uncertain significance ★★ same condition
NPRL2 p.Arg295Gln Uncertain significance ★★ ⚠ same condition
NPRL2 p.Asp201Ala Uncertain significance ★★ ⚠ same condition
NPRL2 p.Leu64Pro Uncertain significance ★★ ⚠ 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/nprl2-p-phe87ser (accessed [today's date]).

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