Is CERK p.Arg232Leu (c.695G>T) pathogenic?

CERK p.Arg232Leu (c.695G>T) is classified Uncertain significance in CERK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-03). AlphaMissense: ambiguous (0.497); Very rare (popmax 0.00339%, nfe).

How common is CERK p.Arg232Leu (c.695G>T) in the general population?

CERK p.Arg232Leu (c.695G>T) is very rare (popmax 0.00339%, nfe) (gnomAD).

What do computational predictors say about CERK p.Arg232Leu (c.695G>T)?

AlphaMissense predicts ambiguous (score 0.497) — an in-silico prediction, not a clinical call.

CERK p.Arg232Leu

c.695G>T · VCV4001268

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.497 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00339%, nfe)

Computational evidence

Protein change
AlphaMissense	0.497	ambiguous
REVEL	0.397	indeterminate
SaProt	LLR -12.57	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 1.1, phastCons 0.91
Regional constraint	o/e 0.94	unconstrained · MANE · 51 kb · p 0.099 · regional, not allelic
Overall
CADD	26.7	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 0.00339% European (non-Finnish) · 40/1,178,846 alleles

Filtering AF 0.00256% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00225%

Overall 0.00254% 41/1,611,948 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00339%	29,471
Finnishnot grpmax-eligible	0.00156%	63,944

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.Arg232Leu
Coding: c.695G>T
MANE Select: NM_022766
Type: single nucleotide variant
Location: chr22:46707863 (GRCh38)
Gene constraint: LOEUF 0.829 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.86
Residue 232: the dagkc domain

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

Similar variants

CERK p.Arg232Trp Uncertain significance ★ ⚠ same residue
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

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-arg232leu (accessed [today's date]).

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