Is CLK2 p.Arg429His (c.1286G>A) pathogenic?

CLK2 p.Arg429His (c.1286G>A) is classified Uncertain significance in CLK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-29). AlphaMissense: ambiguous (0.5097); Ultra-rare (popmax 0.0493%, mid).

How common is CLK2 p.Arg429His (c.1286G>A) in the general population?

CLK2 p.Arg429His (c.1286G>A) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

What do computational predictors say about CLK2 p.Arg429His (c.1286G>A)?

AlphaMissense predicts ambiguous (score 0.5097) — an in-silico prediction, not a clinical call.

CLK2 p.Arg429His

c.1286G>A · rs1314989986 · VCV2595732

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5097 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5097	ambiguous
REVEL	0.121	moderately benign-leaning
SaProt	LLR -11.51	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 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 1,041 bp · p 0.32 · regional, not allelic
Overall
CADD	27.9	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 0.0493% Middle Eastern · 3/6,084 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00715%

Overall 0.00161% 26/1,614,034 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,028
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Finnishnot grpmax-eligible	0.00312%	32,015
East Asian	0.00223%	44,890
South Asian	0.0022%	45,544
European (non-Finnish)	0.00144%	69,414

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.Arg429His
Coding: c.1286G>A
MANE Select: NM_001294338
dbSNP: rs1314989986
Type: single nucleotide variant
Location: chr1:155263981 (GRCh38)
Gene constraint: LOEUF 0.273 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.61 · 6 PDB
Residue 429: 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.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
CLK2 p.Arg120Gln 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-arg429his (accessed [today's date]).

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