Is NEK3 p.Gln22Pro (c.65A>C) pathogenic?

NEK3 p.Gln22Pro (c.65A>C) is classified Uncertain significance in NEK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: ambiguous (0.3811); Very rare (popmax 0.00223%, sas).

How common is NEK3 p.Gln22Pro (c.65A>C) in the general population?

NEK3 p.Gln22Pro (c.65A>C) is very rare (popmax 0.00223%, sas) (gnomAD).

What do computational predictors say about NEK3 p.Gln22Pro (c.65A>C)?

AlphaMissense predicts ambiguous (score 0.3811) — an in-silico prediction, not a clinical call.

NEK3 p.Gln22Pro

c.65A>C · VCV4118641

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3811 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3811	ambiguous
REVEL	0.238	benign-leaning
SaProt	LLR -13.05	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.83	GERP -3, phastCons 0.001
Regional constraint	o/e 0.98	unconstrained · MANE · 23 kb · p 0.68 · regional, not allelic
Overall
CADD	14.72	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% South Asian · 2/89,518 alleles

Filtering AF 0.000371% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000139%

Overall 0.000124% 2/1,608,542 alleles · very rare exomes 2/1,456,220 · genomes 0/152,322 · 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: NEK3
Protein: p.Gln22Pro
Coding: c.65A>C
MANE Select: NM_002498
Type: single nucleotide variant
Location: chr13:52156127 (GRCh38)
Gene constraint: LOEUF 0.935 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.52
Residue 22: the protein kinase domain; the 'interaction with vav2' region

Full NEK3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NEK3 p.Arg259Gly Benign ★★ same type
NEK3 p.Ala204Val Uncertain significance ★ ⚠ same type
NEK3 p.Ala258Val Uncertain significance ★ ⚠ same type
NEK3 p.Ala55Val Uncertain significance ★ same type
NEK3 p.Ala71Gly Uncertain significance ★ ⚠ same type
NEK3 p.Arg122Cys Uncertain significance ★ ⚠ same type
NEK3 p.Arg150Cys Uncertain significance ★ ⚠ same type
NEK3 p.Arg150His 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/nek3-p-gln22pro (accessed [today's date]).

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