Is CLK4 p.Arg29Pro (c.86G>C) pathogenic?

CLK4 p.Arg29Pro (c.86G>C) is classified Uncertain significance in CLK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: ambiguous (0.4719); Very rare (popmax 0.00668%, afr).

How common is CLK4 p.Arg29Pro (c.86G>C) in the general population?

CLK4 p.Arg29Pro (c.86G>C) is very rare (popmax 0.00668%, afr) (gnomAD).

What do computational predictors say about CLK4 p.Arg29Pro (c.86G>C)?

AlphaMissense predicts ambiguous (score 0.4719) — an in-silico prediction, not a clinical call.

CLK4 p.Arg29Pro

c.86G>C · VCV4230023

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4719 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4719	ambiguous
REVEL	0.219	benign-leaning
SaProt	LLR -9.20	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 20 kb · p 1.7e-09 · regional, not allelic
Overall
CADD	26.4	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 0.00668% African / African-American · 5/74,906 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.00031% 5/1,613,890 alleles · very rare

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: CLK4
Protein: p.Arg29Pro
Coding: c.86G>C
MANE Select: NM_020666
Type: single nucleotide variant
Location: chr5:178623331 (GRCh38)
Gene constraint: LOEUF 0.87 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.48 · 1 PDB
Residue 29: the 'disordered' region

Full CLK4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLK4 p.Arg29Trp Uncertain significance ★ ⚠ same residue
CLK4 p.Ala469Gly Uncertain significance ★ ⚠ same type
CLK4 p.Arg110Gly Uncertain significance ★ ⚠ same type
CLK4 p.Arg117His Uncertain significance ★ ⚠ same type
CLK4 p.Arg156Lys Uncertain significance ★ ⚠ same type
CLK4 p.Arg198Cys Uncertain significance ★ ⚠ same type
CLK4 p.Arg202Cys Uncertain significance ★ ⚠ same type
CLK4 p.Arg221Gln 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/clk4-p-arg29pro (accessed [today's date]).

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