Is CES1 p.Val166Met (c.496G>A) pathogenic?

CES1 p.Val166Met (c.496G>A) is classified Uncertain significance in CES1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-18). AlphaMissense: likely benign (0.3166); Very rare (popmax 0.00667%, amr); Associated with CES1-related condition.

What condition is associated with CES1 p.Val166Met (c.496G>A)?

CES1 p.Val166Met (c.496G>A) is associated with CES1-related condition (ClinVar).

How common is CES1 p.Val166Met (c.496G>A) in the general population?

CES1 p.Val166Met (c.496G>A) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about CES1 p.Val166Met (c.496G>A)?

AlphaMissense predicts likely benign (score 0.3166) — an in-silico prediction, not a clinical call.

CES1 p.Val166Met

c.496G>A · rs762888069 · VCV3143228

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3166 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CES1-related condition

Computational evidence

Protein change
AlphaMissense	0.3166	likely benign
REVEL	0.309	indeterminate
SaProt	LLR -11.57	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP 0.85, phastCons 0.43
Regional constraint	o/e 0.08	constrained · MANE · 2,576 bp · p 7.7e-11 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V165M vs ClinVar V166M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/60,008 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000372% 6/1,613,876 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,002
Remaining individualsnot grpmax-eligible	0.0032%	31,232

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: CES1
Protein: p.Val166Met
Coding: c.496G>A
MANE Select: NM_001025195
dbSNP: rs762888069
Type: single nucleotide variant
Location: chr16:55823593 (GRCh38)
Gene constraint: LOEUF 1.272 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.27 · 21 PDB
Residue 166: a β-strand

Full CES1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CES1-related condition

Similar variants

CES1 p.Ala45Val Uncertain significance ★ ⚠ same condition
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/ces1-p-val166met (accessed [today's date]).

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