Is CLK3 p.Val191Met (c.571G>A) pathogenic?

CLK3 p.Val191Met (c.571G>A) is classified Uncertain significance in CLK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-05). AlphaMissense: likely pathogenic (0.9568); Very rare (popmax 0.00133%, afr).

How common is CLK3 p.Val191Met (c.571G>A) in the general population?

CLK3 p.Val191Met (c.571G>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CLK3 p.Val191Met (c.571G>A)?

AlphaMissense predicts likely pathogenic (score 0.9568) — an in-silico prediction, not a clinical call.

CLK3 p.Val191Met

c.571G>A · VCV3834063

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9568 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Computational evidence

Protein change
AlphaMissense	0.9568	likely pathogenic
REVEL	0.325	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.1, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 9,706 bp · p 4.3e-15 · regional, not allelic
Overall
CADD	33.0	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 V339M vs ClinVar V191M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,014 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000343% 5/1,459,150 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,438
African / African-Americangrpmax	0.00133%	75,014
European (non-Finnish)	0.000254%	392,954

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CLK3
Protein: p.Val191Met
Coding: c.571G>A
MANE Select: NM_001130028
Type: single nucleotide variant
Location: chr15:74624939 (GRCh38)
Gene constraint: LOEUF 0.505 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 78.27 · 22 PDB
Residue 191: the protein kinase domain

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-val191met (accessed [today's date]).

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