Is CES2 p.Pro141Ala (c.421C>G) pathogenic?

CES2 p.Pro141Ala (c.421C>G) is classified Uncertain significance in CES2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-12). AlphaMissense: likely benign (0.2395); Very rare (popmax 8.47e-05%, nfe).

How common is CES2 p.Pro141Ala (c.421C>G) in the general population?

CES2 p.Pro141Ala (c.421C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CES2 p.Pro141Ala (c.421C>G)?

AlphaMissense predicts likely benign (score 0.2395) — an in-silico prediction, not a clinical call.

CES2 p.Pro141Ala

c.421C>G · rs2544154368 · VCV2318005

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2395 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2395	likely benign
REVEL	0.753	pathogenic-leaning
SaProt	LLR -8.41	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 0.73, phastCons 0.99
Overall
CADD	25.1	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 8.47e-05% European (non-Finnish) · 1/1,179,960 alleles

Overall 6.84e-05% 1/1,461,654 alleles · very rare

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.Pro141Ala
Coding: c.421C>G
MANE Select: NM_001025195 · reported on NM_001365405
dbSNP: rs2544154368
Type: single nucleotide variant
Location: chr16:66939356 (GRCh38)
Structure: AlphaFold pLDDT 93.27 · 21 PDB

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

Similar variants

CES1 p.His141Arg Uncertain significance ★ ⚠ same residue
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

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-pro141ala (accessed [today's date]).

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