Is CES3 p.Ile63Thr (c.188T>C) pathogenic?

CES3 p.Ile63Thr (c.188T>C) is classified Uncertain significance in CES3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-24). AlphaMissense: likely pathogenic (0.9519); Very rare (popmax 0.00534%, afr).

How common is CES3 p.Ile63Thr (c.188T>C) in the general population?

CES3 p.Ile63Thr (c.188T>C) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about CES3 p.Ile63Thr (c.188T>C)?

AlphaMissense predicts likely pathogenic (score 0.9519) — an in-silico prediction, not a clinical call.

CES3 p.Ile63Thr

c.188T>C · VCV4226760

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9519 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9519	likely pathogenic · top 1% in CES3
REVEL	0.373	indeterminate
SaProt	LLR -12.83	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	GERP 1.9, phastCons 0.74
Regional constraint	o/e 0.87	unconstrained · MANE · 12 kb · p 0.00037 · regional, not allelic
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00534% African / African-American · 4/74,906 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00031% 5/1,613,614 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,726
European (non-Finnish)	8.47e-05%	1,180,018

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: CES3
Protein: p.Ile63Thr
Coding: c.188T>C
MANE Select: NM_024922
Type: single nucleotide variant
Location: chr16:66963284 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.89

Full CES3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CES3 p.Ile63Val Uncertain significance ★ ⚠ same residue
CES3 p.Ala133Pro Uncertain significance ★ ⚠ same type
CES3 p.Ala137Thr Uncertain significance ★ ⚠ same type
CES3 p.Ala214Val Uncertain significance ★ ⚠ same type
CES3 p.Ala230Gly Uncertain significance ★ ⚠ same type
CES3 p.Ala244Thr Uncertain significance ★ ⚠ same type
CES3 p.Ala408Glu Uncertain significance ★ ⚠ same type
CES3 p.Ala449Glu 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/ces3-p-ile63thr (accessed [today's date]).

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