Is CES3 p.Val203Glu (c.608T>A) pathogenic?

CES3 p.Val203Glu (c.608T>A) is classified Uncertain significance in CES3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-02). AlphaMissense: ambiguous (0.5555); Ultra-rare (popmax 0.0693%, afr).

How common is CES3 p.Val203Glu (c.608T>A) in the general population?

CES3 p.Val203Glu (c.608T>A) is ultra-rare (popmax 0.0693%, afr) (gnomAD).

What do computational predictors say about CES3 p.Val203Glu (c.608T>A)?

AlphaMissense predicts ambiguous (score 0.5555) — an in-silico prediction, not a clinical call.

CES3 p.Val203Glu

c.608T>A · rs182464715 · VCV2513864

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5555 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0693%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5555	ambiguous
REVEL	0.71	pathogenic-leaning
SaProt	LLR -12.72	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP 0.84, phastCons 0.83
Regional constraint	o/e 0.87	unconstrained · MANE · 12 kb · p 0.00037 · regional, not allelic
Overall
CADD	24.0	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 0.0693% African / African-American · 52/75,052 alleles

Filtering AF 0.0542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0489%

Overall 0.00347% 56/1,614,094 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0693%	1,443
Admixed American	0.00333%	30,009
Remaining individualsnot grpmax-eligible	0.0032%	31,253

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.Val203Glu
Coding: c.608T>A
MANE Select: NM_024922
dbSNP: rs182464715
Type: single nucleotide variant
Location: chr16:66964404 (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.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
CES3 p.Ala449Val 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-val203glu (accessed [today's date]).

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