Is CES3 p.Thr319Ser (c.955A>T) pathogenic?

CES3 p.Thr319Ser (c.955A>T) is classified Uncertain significance in CES3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-25). AlphaMissense: likely benign (0.1045); Very rare (popmax 0.00133%, afr).

How common is CES3 p.Thr319Ser (c.955A>T) in the general population?

CES3 p.Thr319Ser (c.955A>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CES3 p.Thr319Ser (c.955A>T)?

AlphaMissense predicts likely benign (score 0.1045) — an in-silico prediction, not a clinical call.

CES3 p.Thr319Ser

c.955A>T · rs1963738042 · VCV2360223

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1045 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1045	likely benign
REVEL	0.05	moderately benign-leaning
SaProt	LLR -8.49	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.30	acceptor gain · deltas
Constraint at this position
Conservation	phyloP -3.8	GERP -3.7
Regional constraint	o/e 0.87	unconstrained · MANE · 12 kb · p 0.00037 · regional, not allelic
Overall
CADD	5.299	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 0.00133% African / African-American · 1/75,022 alleles

Overall 0.000137% 2/1,461,870 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,510
African / African-Americangrpmax	0.00133%	75,022

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Thr319Ser
Coding: c.955A>T
MANE Select: NM_024922
dbSNP: rs1963738042
Type: single nucleotide variant
Location: chr16:66966758 (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-thr319ser (accessed [today's date]).

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