Is CES1 p.Pro333Ser (c.997C>T) pathogenic?

CES1 p.Pro333Ser (c.997C>T) is classified Uncertain significance in CES1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-22). AlphaMissense: ambiguous (0.4851); Very rare (popmax 0.00833%, amr).

How common is CES1 p.Pro333Ser (c.997C>T) in the general population?

CES1 p.Pro333Ser (c.997C>T) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about CES1 p.Pro333Ser (c.997C>T)?

AlphaMissense predicts ambiguous (score 0.4851) — an in-silico prediction, not a clinical call.

CES1 p.Pro333Ser

c.997C>T · VCV4652673

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4851 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Computational evidence

Protein change
AlphaMissense	0.4851	ambiguous
REVEL	0.472	indeterminate
SaProt	LLR -12.46	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.5, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 17 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	22.9	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 P332S vs ClinVar P333S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00833% Admixed American · 5/60,000 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000558% 9/1,613,894 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,000
African / African-American	0.00134%	74,864
European (non-Finnish)	0.000254%	393,315

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.Pro333Ser
Coding: c.997C>T
MANE Select: NM_001025195
Type: single nucleotide variant
Location: chr16:55812992 (GRCh38)
Gene constraint: LOEUF 1.272 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.27 · 21 PDB
Residue 333: an α-helix

Full CES1 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/ces1-p-pro333ser (accessed [today's date]).

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