Is CLK1 p.Pro307Ser (c.919C>T) pathogenic?

CLK1 p.Pro307Ser (c.919C>T) is classified Uncertain significance in CLK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-05). AlphaMissense: likely benign (0.1254); Very rare (popmax 0.00333%, amr).

How common is CLK1 p.Pro307Ser (c.919C>T) in the general population?

CLK1 p.Pro307Ser (c.919C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about CLK1 p.Pro307Ser (c.919C>T)?

AlphaMissense predicts likely benign (score 0.1254) — an in-silico prediction, not a clinical call.

CLK1 p.Pro307Ser

c.919C>T · VCV4229972

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1254 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1254	likely benign
REVEL	0.074	moderately benign-leaning
SaProt	LLR -7.60	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 3.5	GERP 0.19, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 6,820 bp · p 0.02 · regional, not allelic
Overall
CADD	15.34	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 0.00333% Admixed American · 2/60,004 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00124% 20/1,613,944 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,002
European (non-Finnish)	0.00153%	65,553

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: CLK1
Protein: p.Pro307Ser
Coding: c.919C>T
MANE Select: NM_004071
Type: single nucleotide variant
Location: chr2:200856899 (GRCh38)
Gene constraint: LOEUF 0.776 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.56 · 38 PDB
Residue 307: the protein kinase domain; a UniProt-annotated variant site (in); a turn

Full CLK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLK1 c.-1+345C>T Uncertain significance ★ same type
CLK1 c.-1+363C>G Uncertain significance ★ same type
CLK1 c.-1+371T>C Uncertain significance ★ same type
CLK1 c.-1+383C>G Uncertain significance ★ same type
CLK1 c.-1+387G>A Uncertain significance ★ same type
CLK1 c.-1+397G>C Uncertain significance ★ same type
CLK1 c.-1+404G>A Uncertain significance ★ same type
CLK1 c.-1+449G>A 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/clk1-p-pro307ser (accessed [today's date]).

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