Is CLK3 p.Glu249Ala (c.746A>C) pathogenic?

CLK3 p.Glu249Ala (c.746A>C) is classified Uncertain significance in CLK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-26). AlphaMissense: likely pathogenic (0.8409); Absent from gnomAD v4.1.

How common is CLK3 p.Glu249Ala (c.746A>C) in the general population?

CLK3 p.Glu249Ala (c.746A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLK3 p.Glu249Ala (c.746A>C)?

AlphaMissense predicts likely pathogenic (score 0.8409) — an in-silico prediction, not a clinical call.

CLK3 p.Glu249Ala

c.746A>C · VCV3493782

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8409 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
AlphaMissense	0.8409	likely pathogenic
REVEL	0.416	indeterminate
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.82 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 9,706 bp · p 4.3e-15 · 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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM E397A vs ClinVar E249A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CLK3
Protein: p.Glu249Ala
Coding: c.746A>C
MANE Select: NM_001130028
Type: single nucleotide variant
Location: chr15:74625897 (GRCh38)
Gene constraint: LOEUF 0.505 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 78.27 · 22 PDB
Residue 249: the protein kinase domain; an α-helix

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

Similar variants

CLK3 p.Pro89Arg Uncertain significance ★★ ⚠ same type
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

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-glu249ala (accessed [today's date]).

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