Is CES5A p.Pro65Ser (c.193C>T) pathogenic?

CES5A p.Pro65Ser (c.193C>T) is classified Uncertain significance in CES5A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-28). AlphaMissense: likely benign (0.1742); Very rare (popmax 0.0011%, sas).

How common is CES5A p.Pro65Ser (c.193C>T) in the general population?

CES5A p.Pro65Ser (c.193C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CES5A p.Pro65Ser (c.193C>T)?

AlphaMissense predicts likely benign (score 0.1742) — an in-silico prediction, not a clinical call.

CES5A p.Pro65Ser

c.193C>T · rs1230406058 · VCV2621559

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1742 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1742	likely benign
REVEL	0.379	indeterminate
SaProt	LLR -11.53	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.9, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 29 kb · p 0.14 · regional, not allelic
Overall
CADD	22.9	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 0.0011% South Asian · 1/90,876 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000434% 7/1,613,916 alleles · very rare exomes 7/1,461,554 · genomes 0/152,362 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	90,876
European (non-Finnish)	0.000508%	196,669

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: CES5A
Protein: p.Pro65Ser
Coding: c.193C>T
MANE Select: NM_001143685
dbSNP: rs1230406058
Type: single nucleotide variant
Location: chr16:55873918 (GRCh38)
Gene constraint: LOEUF 1.26 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.48

Full CES5A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CES5A p.Leu527= Benign ★★ same type
CES5A p.Ala154Gly Uncertain significance ★ ⚠ same type
CES5A p.Ala195Val Uncertain significance ★ ⚠ same type
CES5A p.Ala262Thr Uncertain significance ★ ⚠ same type
CES5A p.Ala282Val Uncertain significance ★ ⚠ same type
CES5A p.Ala334Thr Uncertain significance ★ ⚠ same type
CES5A p.Ala465Gly Uncertain significance ★ ⚠ same type
CES5A p.Ala465Pro 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/ces5a-p-pro65ser (accessed [today's date]).

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