Is NEK2 p.Ser296Pro (c.886T>C) pathogenic?

NEK2 p.Ser296Pro (c.886T>C) is classified Uncertain significance in NEK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-10). AlphaMissense: likely benign (0.0508); Very rare (popmax 8.48e-05%, nfe).

How common is NEK2 p.Ser296Pro (c.886T>C) in the general population?

NEK2 p.Ser296Pro (c.886T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about NEK2 p.Ser296Pro (c.886T>C)?

AlphaMissense predicts likely benign (score 0.0508) — an in-silico prediction, not a clinical call.

NEK2 p.Ser296Pro

c.886T>C · rs924484677 · VCV2799087

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0508 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0508	likely benign
REVEL	0.168	moderately benign-leaning
SaProt	LLR -6.49	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.51	GERP -4.1
Regional constraint	o/e 0.77	unconstrained · MANE · 12 kb · p 6.7e-08 · regional, not allelic
Overall
CADD	4.61	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 8.48e-05% European (non-Finnish) · 1/1,179,892 alleles

Overall 6.2e-05% 1/1,613,832 alleles · very rare exomes 1/1,461,694 · genomes 0/152,138 · 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: NEK2
Protein: p.Ser296Pro
Coding: c.886T>C
MANE Select: NM_002497
dbSNP: rs924484677
Type: single nucleotide variant
Location: chr1:211669212 (GRCh38)
Gene constraint: LOEUF 0.648 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 78.52 · 30 PDB
Residue 296: a modified residue (phosphoserine); the 'interaction with pcnt' region

Full NEK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NEK2 p.Ser296= Benign/Likely benign ★★ same residue
NEK2 c.97-2A>G Uncertain significance ★★ same type
NEK2 p.Arg130Gln Uncertain significance ★★ same type
NEK2 p.Arg130Gly Uncertain significance ★★ ⚠ same type
NEK2 p.Arg140Gln Uncertain significance ★★ ⚠ same type
NEK2 p.Arg239His Uncertain significance ★★ ⚠ same type
NEK2 p.Arg239Ser Uncertain significance ★★ ⚠ same type
NEK2 p.Arg318Gln Uncertain significance ★★ ⚠ same type

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/nek2-p-ser296pro (accessed [today's date]).

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