Is CLK4 p.Arg156Lys (c.467G>A) pathogenic?

CLK4 p.Arg156Lys (c.467G>A) is classified Uncertain significance in CLK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). AlphaMissense: likely benign (0.128); Ultra-rare (popmax 0.026%, nfe).

How common is CLK4 p.Arg156Lys (c.467G>A) in the general population?

CLK4 p.Arg156Lys (c.467G>A) is ultra-rare (popmax 0.026%, nfe) (gnomAD).

What do computational predictors say about CLK4 p.Arg156Lys (c.467G>A)?

AlphaMissense predicts likely benign (score 0.128) — an in-silico prediction, not a clinical call.

CLK4 p.Arg156Lys

c.467G>A · rs142915100 · VCV2344916

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.128 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.026%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.128	likely benign
REVEL	0.096	moderately benign-leaning
SaProt	LLR -5.58	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 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 20 kb · p 1.7e-09 · regional, not allelic
Overall
CADD	23.6	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 0.026% European (non-Finnish) · 306/1,177,714 alleles

Filtering AF 0.0235% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0226%

Overall 0.0218% 351/1,611,450 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.026%	3,849
South Asian	0.0242%	4,138
African / African-American	0.012%	8,318
Remaining individualsnot grpmax-eligible	0.0112%	8,911
Admixed American	0.00667%	14,999
Finnishnot grpmax-eligible	0.00469%	21,339

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.Arg156Lys
Coding: c.467G>A
MANE Select: NM_020666
dbSNP: rs142915100
Type: single nucleotide variant
Location: chr5:178617352 (GRCh38)
Gene constraint: LOEUF 0.87 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.48 · 1 PDB
Residue 156: a turn

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.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
CLK4 p.Arg29Pro 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-arg156lys (accessed [today's date]).

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