Is CES2 p.Met415Val (c.1243A>G) pathogenic?

CES2 p.Met415Val (c.1243A>G) is classified Uncertain significance in CES2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-05). AlphaMissense: likely benign (0.0871); Ultra-rare (popmax 0.0164%, nfe).

How common is CES2 p.Met415Val (c.1243A>G) in the general population?

CES2 p.Met415Val (c.1243A>G) is ultra-rare (popmax 0.0164%, nfe) (gnomAD).

What do computational predictors say about CES2 p.Met415Val (c.1243A>G)?

AlphaMissense predicts likely benign (score 0.0871) — an in-silico prediction, not a clinical call.

CES2 p.Met415Val

c.1243A>G · VCV3491083

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0871 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0871	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -5.89	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 -8.2	GERP -3.1
Overall
CADD	0.03	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 0.0164% European (non-Finnish) · 194/1,179,776 alleles

Filtering AF 0.0145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0138%

Overall 0.0129% 208/1,613,614 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0224%	4,462
European (non-Finnish)grpmax	0.0164%	6,081

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Met415Val
Coding: c.1243A>G
MANE Select: NM_001025195 · reported on NM_001365405
Type: single nucleotide variant
Location: chr16:66942210 (GRCh38)
Structure: AlphaFold pLDDT 93.27 · 21 PDB
Residue 415: 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-met415val (accessed [today's date]).

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