Is CES1 p.Leu97Phe (c.291A>T) pathogenic?

CES1 p.Leu97Phe (c.291A>T) is classified Likely benign in CES1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-05). AlphaMissense: likely benign (0.1112); Ultra-rare (popmax 0.0707%, afr).

How common is CES1 p.Leu97Phe (c.291A>T) in the general population?

CES1 p.Leu97Phe (c.291A>T) is ultra-rare (popmax 0.0707%, afr) (gnomAD).

What do computational predictors say about CES1 p.Leu97Phe (c.291A>T)?

AlphaMissense predicts likely benign (score 0.1112) — an in-silico prediction, not a clinical call.

CES1 p.Leu97Phe

c.291A>T · rs375565319 · VCV2589332

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1112 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0707%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1112	likely benign
REVEL	0.012	strongly benign-leaning
SaProt	LLR -5.90	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 -12	GERP -3.4
Regional constraint	o/e 1.01	unconstrained · MANE · 6,902 bp · p 0.9 · regional, not allelic
Overall
CADD	0.001	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 L96F vs ClinVar L97F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0707% African / African-American · 53/74,990 alleles

Filtering AF 0.0554% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0501%

Overall 0.00564% 91/1,613,900 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0707%	1,415
Admixed American	0.00333%	30,008
South Asian	0.00329%	30,357
Remaining individualsnot grpmax-eligible	0.0032%	31,244
European (non-Finnish)	0.00254%	39,328
East Asian	0.00223%	44,886

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.Leu97Phe
Coding: c.291A>T
MANE Select: NM_001025195
dbSNP: rs375565319
Type: single nucleotide variant
Location: chr16:55826265 (GRCh38)
Gene constraint: LOEUF 1.272 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.27 · 21 PDB
Residue 97: an α-helix; a disulfide bond

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

Similar variants

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
CES1 p.Ala197Asp Uncertain significance ★ ⚠ same type
CES1 p.Ala338Gly 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-leu97phe (accessed [today's date]).

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