Is CLK3 p.Pro89Arg (c.266C>G) pathogenic?

CLK3 p.Pro89Arg (c.266C>G) is classified Uncertain significance in CLK3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-07-27). AlphaMissense: likely benign (0.0645); Very rare (popmax 0.00729%, sas).

How common is CLK3 p.Pro89Arg (c.266C>G) in the general population?

CLK3 p.Pro89Arg (c.266C>G) is very rare (popmax 0.00729%, sas) (gnomAD).

What do computational predictors say about CLK3 p.Pro89Arg (c.266C>G)?

AlphaMissense predicts likely benign (score 0.0645) — an in-silico prediction, not a clinical call.

CLK3 p.Pro89Arg

c.266C>G · rs1356912577 · VCV2303776

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0645 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00729%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.0645	likely benign
REVEL	0.011	strongly benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 1.1, phastCons 0.99
Overall
CADD	14.84	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00729% South Asian · 2/27,438 alleles

Filtering AF 0.00121% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000451%

Overall 0.000565% 7/1,238,688 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00729%	13,719
Remaining individualsnot grpmax-eligible	0.00435%	22,996
European (non-Finnish)	0.000303%	330,404

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: CLK3
Protein: p.Pro89Arg
Coding: c.266C>G
MANE Select: NM_001130028
dbSNP: rs1356912577
Type: single nucleotide variant
Location: chr15:74615720 (GRCh38)
Gene constraint: LOEUF 0.505 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 78.27 · 22 PDB
Residue 89: the 'disordered' region

Full CLK3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLK3 c.125G>A Uncertain significance ★ same type
CLK3 c.19C>T Uncertain significance ★ same type
CLK3 c.310C>T Uncertain significance ★ same type
CLK3 c.374T>G Uncertain significance ★ same type
CLK3 c.-1+1G>C Uncertain significance ★ same type
CLK3 c.-12G>C Uncertain significance ★ ⚠ same type
CLK3 c.-12G>T Uncertain significance ★ ⚠ same type
CLK3 c.-24G>C 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/clk3-p-pro89arg (accessed [today's date]).

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