Is CES3 p.Val383Met (c.1147G>A) pathogenic?

CES3 p.Val383Met (c.1147G>A) is classified Uncertain significance in CES3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-14). AlphaMissense: likely benign (0.2465); Rare (popmax 0.255%, afr).

How common is CES3 p.Val383Met (c.1147G>A) in the general population?

CES3 p.Val383Met (c.1147G>A) is rare (popmax 0.255%, afr) (gnomAD).

What do computational predictors say about CES3 p.Val383Met (c.1147G>A)?

AlphaMissense predicts likely benign (score 0.2465) — an in-silico prediction, not a clinical call.

CES3 p.Val383Met

c.1147G>A · VCV4226762

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2465 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.255%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2465	likely benign
REVEL	0.015	strongly benign-leaning
SaProt	LLR -9.15	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.4	GERP -2.1
Regional constraint	o/e 0.87	unconstrained · MANE · 12 kb · p 0.00037 · regional, not allelic
Overall
CADD	0.217	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 0.255% African / African-American · 191/75,032 alleles

Filtering AF 0.225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.214%

Overall 0.0133% 214/1,612,492 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.255%	393
Remaining individualsnot grpmax-eligible	0.00961%	10,406
Admixed American	0.00668%	14,978
European (non-Finnish)	0.0011%	90,693

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.Val383Met
Coding: c.1147G>A
MANE Select: NM_024922
Type: single nucleotide variant
Location: chr16:66971175 (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-val383met (accessed [today's date]).

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