Is CLK2 p.Arg418Leu (c.1253G>T) pathogenic?

CLK2 p.Arg418Leu (c.1253G>T) is classified Uncertain significance in CLK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-01). AlphaMissense: ambiguous (0.441); Very rare (popmax 0.0011%, sas).

How common is CLK2 p.Arg418Leu (c.1253G>T) in the general population?

CLK2 p.Arg418Leu (c.1253G>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CLK2 p.Arg418Leu (c.1253G>T)?

AlphaMissense predicts ambiguous (score 0.441) — an in-silico prediction, not a clinical call.

CLK2 p.Arg418Leu

c.1253G>T · rs777248821 · VCV2330263

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.441 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.441	ambiguous
REVEL	0.158	moderately benign-leaning
SaProt	LLR -12.82	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.42	GERP 0.031, phastCons 0.52
Regional constraint	o/e 0.92	unconstrained · MANE · 1,041 bp · p 0.32 · regional, not allelic
Overall
CADD	22.9	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 0.0011% South Asian · 1/91,072 alleles

Overall 0.000186% 3/1,613,982 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,022
South Asiangrpmax	0.0011%	91,072
European (non-Finnish)	8.47e-05%	1,179,994

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CLK2
Protein: p.Arg418Leu
Coding: c.1253G>T
MANE Select: NM_001294338
dbSNP: rs777248821
Type: single nucleotide variant
Location: chr1:155264014 (GRCh38)
Gene constraint: LOEUF 0.273 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.61 · 6 PDB
Residue 418: the protein kinase domain

Full CLK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLK2 p.Arg418Cys Uncertain significance ★ ⚠ same residue
CLK2 p.Ala140Pro Uncertain significance ★ ⚠ same type
CLK2 p.Ala188Val Uncertain significance ★ ⚠ same type
CLK2 p.Ala480Val Uncertain significance ★ ⚠ same type
CLK2 p.Arg103Gln Uncertain significance ★ ⚠ same type
CLK2 p.Arg109Cys Uncertain significance ★ ⚠ same type
CLK2 p.Arg112Cys Uncertain significance ★ ⚠ same type
CLK2 p.Arg115Gln 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/clk2-p-arg418leu (accessed [today's date]).

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