Is CLK3 p.Pro44Arg (c.131C>G) pathogenic?

CLK3 p.Pro44Arg (c.131C>G) is classified Uncertain significance in CLK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-06). AlphaMissense: likely benign (0.2746); Ultra-rare (popmax 0.0164%, mid).

How common is CLK3 p.Pro44Arg (c.131C>G) in the general population?

CLK3 p.Pro44Arg (c.131C>G) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CLK3 p.Pro44Arg (c.131C>G)?

AlphaMissense predicts likely benign (score 0.2746) — an in-silico prediction, not a clinical call.

CLK3 p.Pro44Arg

c.131C>G · VCV3834069

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2746 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.2746	likely benign
REVEL	0.111	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.6, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 976 bp · p 0.088 · regional, not allelic
Overall
CADD	21.7	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 is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P192R vs ClinVar P44R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00112% 18/1,614,040 alleles · ultra-rare exomes 17/1,461,834 · genomes 1/152,206 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Admixed American	0.00167%	60,004
African / African-American	0.00133%	74,924
European (non-Finnish)	0.00119%	84,286
South Asian	0.0011%	91,080

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.Pro44Arg
Coding: c.131C>G
MANE Select: NM_001130028
Type: single nucleotide variant
Location: chr15:74619327 (GRCh38)
Gene constraint: LOEUF 0.505 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 78.27 · 22 PDB

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-pro44arg (accessed [today's date]).

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