Is CERK p.Pro45Ser (c.133C>T) pathogenic?

CERK p.Pro45Ser (c.133C>T) is classified Uncertain significance in CERK (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-16). AlphaMissense: likely benign (0.0975); Very rare (popmax 0.000624%, nfe).

How common is CERK p.Pro45Ser (c.133C>T) in the general population?

CERK p.Pro45Ser (c.133C>T) is very rare (popmax 0.000624%, nfe) (gnomAD).

What do computational predictors say about CERK p.Pro45Ser (c.133C>T)?

AlphaMissense predicts likely benign (score 0.0975) — an in-silico prediction, not a clinical call.

CERK p.Pro45Ser

c.133C>T · VCV3266320

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0975 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000624%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0975	likely benign
REVEL	0.028	moderately benign-leaning
SaProt	LLR -10.12	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 0.72, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 51 kb · p 0.099 · regional, not allelic
Overall
CADD	19.58	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000624% European (non-Finnish) · 6/962,118 alleles

Filtering AF 0.000224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000147%

Overall 0.000506% 6/1,186,676 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: CERK
Protein: p.Pro45Ser
Coding: c.133C>T
MANE Select: NM_022766
Type: single nucleotide variant
Location: chr22:46738016 (GRCh38)
Gene constraint: LOEUF 0.829 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.86
Residue 45: the 'required for binding to sulfatide and phosphoinositides' region; the 'essential for enzyme activity' region

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

Similar variants

CERK p.His113= Benign ★★ same type
CERK p.Pro509= Benign ★★ same type
CERK p.Thr461Met Benign ★★ same type
CERK p.Ala215Thr Uncertain significance ★ ⚠ same type
CERK p.Ala215Val Uncertain significance ★ ⚠ same type
CERK p.Ala238Ser Uncertain significance ★ ⚠ same type
CERK p.Ala238Thr Uncertain significance ★ ⚠ same type
CERK p.Ala254Thr 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/cerk-p-pro45ser (accessed [today's date]).

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