Is CES2 p.Glu77Ala (c.230A>C) pathogenic?

CES2 p.Glu77Ala (c.230A>C) is classified Uncertain significance in CES2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-12). AlphaMissense: likely benign (0.1447); Ultra-rare (popmax 0.056%, sas).

How common is CES2 p.Glu77Ala (c.230A>C) in the general population?

CES2 p.Glu77Ala (c.230A>C) is ultra-rare (popmax 0.056%, sas) (gnomAD).

What do computational predictors say about CES2 p.Glu77Ala (c.230A>C)?

AlphaMissense predicts likely benign (score 0.1447) — an in-silico prediction, not a clinical call.

CES2 p.Glu77Ala

c.230A>C · rs546877641 · VCV2282208

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1447 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.056%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1447	likely benign
REVEL	0.371	indeterminate
SaProt	LLR -9.33	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 1.9, phastCons 1
Overall
CADD	24.0	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 0.056% South Asian · 51/91,078 alleles

Filtering AF 0.0437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0394%

Overall 0.00366% 59/1,614,122 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.056%	1,786
Admixed American	0.00833%	12,005
Remaining individualsnot grpmax-eligible	0.0032%	31,255
European (non-Finnish)	8.47e-05%	1,180,013

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.Glu77Ala
Coding: c.230A>C
MANE Select: NM_001025195 · reported on NM_001365405
dbSNP: rs546877641
Type: single nucleotide variant
Location: chr16:66938190 (GRCh38)
Structure: AlphaFold pLDDT 93.27 · 21 PDB
Residue 77: a β-strand

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-glu77ala (accessed [today's date]).

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