Is CLK2 p.Arg403Gln (c.1208G>A) pathogenic?

CLK2 p.Arg403Gln (c.1208G>A) is classified Uncertain significance in CLK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-27). AlphaMissense: ambiguous (0.4368); Very rare (popmax 0.00267%, afr).

How common is CLK2 p.Arg403Gln (c.1208G>A) in the general population?

CLK2 p.Arg403Gln (c.1208G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CLK2 p.Arg403Gln (c.1208G>A)?

AlphaMissense predicts ambiguous (score 0.4368) — an in-silico prediction, not a clinical call.

CLK2 p.Arg403Gln

c.1208G>A · rs752431100 · VCV2286280

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4368 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Computational evidence

Protein change
AlphaMissense	0.4368	ambiguous
REVEL	0.375	indeterminate
SaProt	LLR -11.39	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.32	loss · gain 0.01 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 6	GERP -2.3, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 1,041 bp · p 0.32 · regional, not allelic
Overall
CADD	32.0	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 0.00267% African / African-American · 2/74,890 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000743% 12/1,613,998 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,445
Admixed American	0.00167%	60,002
Remaining individualsnot grpmax-eligible	0.0016%	62,488
South Asian	0.0011%	91,084
European (non-Finnish)	0.000593%	168,575

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.Arg403Gln
Coding: c.1208G>A
MANE Select: NM_001294338
dbSNP: rs752431100
Type: single nucleotide variant
Location: chr1:155264239 (GRCh38)
Gene constraint: LOEUF 0.273 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.61 · 6 PDB
Residue 403: the protein kinase domain; an α-helix

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

Similar variants

CLK2 p.Arg403Pro 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-arg403gln (accessed [today's date]).

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