Is CLK4 p.Val321Ala (c.962T>C) pathogenic?

CLK4 p.Val321Ala (c.962T>C) is classified Uncertain significance in CLK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). AlphaMissense: likely pathogenic (0.973); Very rare (popmax 8.47e-05%, nfe).

How common is CLK4 p.Val321Ala (c.962T>C) in the general population?

CLK4 p.Val321Ala (c.962T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CLK4 p.Val321Ala (c.962T>C)?

AlphaMissense predicts likely pathogenic (score 0.973) — an in-silico prediction, not a clinical call.

CLK4 p.Val321Ala

c.962T>C · VCV4654468

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.973 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.973	likely pathogenic
REVEL	0.369	indeterminate
SaProt	LLR -12.83	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 1.1, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 20 kb · p 1.7e-09 · regional, not allelic
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.47e-05% European (non-Finnish) · 1/1,179,972 alleles

Overall 6.84e-05% 1/1,461,800 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.Val321Ala
Coding: c.962T>C
MANE Select: NM_020666
Type: single nucleotide variant
Location: chr5:178612505 (GRCh38)
Gene constraint: LOEUF 0.87 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.48 · 1 PDB
Residue 321: 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-val321ala (accessed [today's date]).

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