Is CES1 p.Arg200Ser (c.598C>A) pathogenic?

CES1 p.Arg200Ser (c.598C>A) is classified Uncertain significance in CES1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). AlphaMissense: likely benign (0.3389); Ultra-rare (popmax 0.0214%, afr).

How common is CES1 p.Arg200Ser (c.598C>A) in the general population?

CES1 p.Arg200Ser (c.598C>A) is ultra-rare (popmax 0.0214%, afr) (gnomAD).

What do computational predictors say about CES1 p.Arg200Ser (c.598C>A)?

AlphaMissense predicts likely benign (score 0.3389) — an in-silico prediction, not a clinical call.

CES1 p.Arg200Ser

c.598C>A · VCV4226717

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3389 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0214%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3389	likely benign
REVEL	0.283	benign-leaning
SaProt	LLR -10.72	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.8, phastCons 0.99
Regional constraint	o/e 1.04	unconstrained · MANE · 3,105 bp · p 0.73 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R199S vs ClinVar R200S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0214% African / African-American · 16/74,894 alleles

Filtering AF 0.0133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0109%

Overall 0.00167% 27/1,614,046 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0214%	4,681
Admixed American	0.0133%	7,500
Remaining individualsnot grpmax-eligible	0.0048%	20,830

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: CES1
Protein: p.Arg200Ser
Coding: c.598C>A
MANE Select: NM_001025195
Type: single nucleotide variant
Location: chr16:55821463 (GRCh38)
Gene constraint: LOEUF 1.272 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.27 · 21 PDB
Residue 200: an α-helix

Full CES1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CES2 p.Asp200Gly Uncertain significance ★ ⚠ same residue
CES1 p.Arg200His Likely benign ★ same residue
CES1 p.Val166Met Uncertain significance ★★ ⚠ same type
CES2 p.Glu366= Benign ★★ same type
CES1 p.Ala126Asp Uncertain significance ★ ⚠ same type
CES1 p.Ala126Val Uncertain significance ★ ⚠ same type
CES1 p.Ala149Glu Uncertain significance ★ ⚠ same type
CES1 p.Ala160Thr 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/ces1-p-arg200ser (accessed [today's date]).

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