Is CLK4 p.Val191Ile (c.571G>A) pathogenic?

CLK4 p.Val191Ile (c.571G>A) is classified Uncertain significance in CLK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-28). AlphaMissense: likely benign (0.1128); Ultra-rare (popmax 0.05%, amr).

How common is CLK4 p.Val191Ile (c.571G>A) in the general population?

CLK4 p.Val191Ile (c.571G>A) is ultra-rare (popmax 0.05%, amr) (gnomAD).

What do computational predictors say about CLK4 p.Val191Ile (c.571G>A)?

AlphaMissense predicts likely benign (score 0.1128) — an in-silico prediction, not a clinical call.

CLK4 p.Val191Ile

c.571G>A · rs187082686 · VCV2341001

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1128 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.05%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1128	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -4.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 1.5, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 20 kb · p 1.7e-09 · regional, not allelic
Overall
CADD	17.25	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 0.05% Admixed American · 30/59,996 alleles

Filtering AF 0.0359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0312%

Overall 0.00254% 41/1,613,840 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.05%	2,000
Remaining individualsnot grpmax-eligible	0.0096%	10,415
African / African-American	0.004%	25,001
European (non-Finnish)	0.00017%	589,922

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.Val191Ile
Coding: c.571G>A
MANE Select: NM_020666
dbSNP: rs187082686
Type: single nucleotide variant
Location: chr5:178613815 (GRCh38)
Gene constraint: LOEUF 0.87 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.48 · 1 PDB
Residue 191: the protein kinase domain; a β-strand

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

Similar variants

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
CLK4 p.Arg24His 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-val191ile (accessed [today's date]).

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