Is NLK p.Pro40Arg (c.119C>G) pathogenic?

NLK p.Pro40Arg (c.119C>G) is classified Uncertain significance in NLK (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-08). AlphaMissense: likely benign (0.2535); Ultra-rare (popmax 0.0116%, nfe).

How common is NLK p.Pro40Arg (c.119C>G) in the general population?

NLK p.Pro40Arg (c.119C>G) is ultra-rare (popmax 0.0116%, nfe) (gnomAD).

What do computational predictors say about NLK p.Pro40Arg (c.119C>G)?

AlphaMissense predicts likely benign (score 0.2535) — an in-silico prediction, not a clinical call.

NLK p.Pro40Arg

c.119C>G · VCV3405999

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2535 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0116%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2535	likely benign
REVEL	0.371	indeterminate
SaProt	LLR -10.74	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 375 bp · p 0.4 · regional, not allelic
Overall
CADD	28.3	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 0.0116% European (non-Finnish) · 133/1,149,920 alleles

Filtering AF 0.00994% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00928%

Overall 0.0088% 137/1,557,212 alleles · ultra-rare exomes 132/1,405,136 · genomes 5/152,076 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0116%	8,646
Remaining individualsnot grpmax-eligible	0.00496%	20,154
African / African-American	0.00137%	73,244

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: NLK
Protein: p.Pro40Arg
Coding: c.119C>G
MANE Select: NM_016231
Type: single nucleotide variant
Location: chr17:28042992 (GRCh38)
Gene constraint: LOEUF 0.308 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.46
Residue 40: the 'required for interaction with tab2' region; the 'sufficient for interaction with dapk3' region; the 'disordered' region

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

Similar variants

NLK p.Ala117Val Uncertain significance ★ ⚠ same type
NLK p.Ala119Gly Uncertain significance ★ ⚠ same type
NLK p.Ala343Gly Uncertain significance ★ ⚠ same type
NLK p.Ala343Ser Uncertain significance ★ ⚠ same type
NLK p.Ala423Thr Uncertain significance ★ ⚠ same type
NLK p.Ala76Thr Uncertain significance ★ ⚠ same type
NLK p.Ala77Gly Uncertain significance ★ ⚠ same type
NLK p.Ala8Val 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/nlk-p-pro40arg (accessed [today's date]).

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