Is CERK p.Val65Ile (c.193G>A) pathogenic?

CERK p.Val65Ile (c.193G>A) is classified Uncertain significance in CERK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-22). AlphaMissense: likely benign (0.0649); Ultra-rare (popmax 0.05%, amr).

How common is CERK p.Val65Ile (c.193G>A) in the general population?

CERK p.Val65Ile (c.193G>A) is ultra-rare (popmax 0.05%, amr) (gnomAD).

What do computational predictors say about CERK p.Val65Ile (c.193G>A)?

AlphaMissense predicts likely benign (score 0.0649) — an in-silico prediction, not a clinical call.

CERK p.Val65Ile

c.193G>A · VCV4652635

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0649 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.05%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0649	likely benign
REVEL	0.021	moderately benign-leaning
SaProt	LLR -5.05	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 0.066
Regional constraint	o/e 0.94	unconstrained · MANE · 51 kb · p 0.099 · regional, not allelic
Overall
CADD	0.748	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 0.05% Admixed American · 30/59,994 alleles

Filtering AF 0.0359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0312%

Overall 0.00285% 46/1,613,632 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.05%	2,000
South Asian	0.00549%	18,216
Finnishnot grpmax-eligible	0.00156%	63,988
African / African-American	0.00134%	74,890
European (non-Finnish)	0.000763%	131,084

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.Val65Ile
Coding: c.193G>A
MANE Select: NM_022766
Type: single nucleotide variant
Location: chr22:46720965 (GRCh38)
Gene constraint: LOEUF 0.829 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.86
Residue 65: 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-val65ile (accessed [today's date]).

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