Is CES2 p.Glu437Lys (c.1309G>A) pathogenic?

CES2 p.Glu437Lys (c.1309G>A) is classified Uncertain significance in CES2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-26). AlphaMissense: ambiguous (0.5614); Very rare (popmax 0.00314%, nfe).

How common is CES2 p.Glu437Lys (c.1309G>A) in the general population?

CES2 p.Glu437Lys (c.1309G>A) is very rare (popmax 0.00314%, nfe) (gnomAD).

What do computational predictors say about CES2 p.Glu437Lys (c.1309G>A)?

AlphaMissense predicts ambiguous (score 0.5614) — an in-silico prediction, not a clinical call.

CES2 p.Glu437Lys

c.1309G>A · VCV3491088

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5614 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00314%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5614	ambiguous
REVEL	0.566	indeterminate
SaProt	LLR -14.75	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.49 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.2	GERP 0.81, phastCons 1
Overall
CADD	28.7	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 0.00314% European (non-Finnish) · 37/1,180,048 alleles

Filtering AF 0.00231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00202%

Overall 0.00254% 41/1,614,076 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00314%	31,893
East Asian	0.00223%	44,896
South Asian	0.0022%	45,543
Remaining individualsnot grpmax-eligible	0.0016%	62,490

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: CES2
Protein: p.Glu437Lys
Coding: c.1309G>A
MANE Select: NM_001025195 · reported on NM_001365405
Type: single nucleotide variant
Location: chr16:66942674 (GRCh38)
Structure: AlphaFold pLDDT 93.27 · 21 PDB
Residue 437: an α-helix

Full CES2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CES1 p.Val166Met Uncertain significance ★★ ⚠ same type
CES2 p.Glu366= Benign ★★ same type
CES1 p.Ala126Asp Uncertain significance ★ ⚠ same type
CES1 p.Ala126Val Uncertain significance ★ ⚠ same type
CES1 p.Ala149Glu Uncertain significance ★ ⚠ same type
CES1 p.Ala160Thr Uncertain significance ★ ⚠ same type
CES1 p.Ala197Asp Uncertain significance ★ ⚠ same type
CES1 p.Ala338Gly 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/ces2-p-glu437lys (accessed [today's date]).

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