Is NEK2 p.Arg235Ter (c.703C>T) pathogenic?

NEK2 p.Arg235Ter (c.703C>T) is classified Uncertain significance in NEK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-20). Very rare (popmax 0.00133%, afr).

How common is NEK2 p.Arg235Ter (c.703C>T) in the general population?

NEK2 p.Arg235Ter (c.703C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

NEK2 p.Arg235Ter

c.703C>T · rs1655333460 · VCV2100351

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 8
Splicing
SpliceAI	Δ0.88	donor gain · deltas
Pangolin	Δ0.49	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3.2	GERP -3.8, phastCons 1
Overall
CADD	42.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,948 alleles

Overall 0.000186% 3/1,612,276 alleles · very rare exomes 3/1,460,092 · genomes 0/152,184 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,948
South Asian	0.0011%	91,010
European (non-Finnish)	8.49e-05%	1,178,516

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.Arg235Ter
Coding: c.703C>T
MANE Select: NM_002497
dbSNP: rs1655333460
Type: single nucleotide variant
Location: chr1:211670343 (GRCh38)
Gene constraint: LOEUF 0.648 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 78.52 · 30 PDB
Residue 235: the protein kinase domain; an α-helix

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

Similar variants

NEK2 p.Arg235Gln Uncertain significance ★ ⚠ 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-arg235ter (accessed [today's date]).

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