Is CES1 p.Ser280Phe (c.839C>T) pathogenic?

CES1 p.Ser280Phe (c.839C>T) is classified Uncertain significance in CES1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-14). AlphaMissense: likely pathogenic (0.7497); Very rare (popmax 0.00223%, eas).

How common is CES1 p.Ser280Phe (c.839C>T) in the general population?

CES1 p.Ser280Phe (c.839C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CES1 p.Ser280Phe (c.839C>T)?

AlphaMissense predicts likely pathogenic (score 0.7497) — an in-silico prediction, not a clinical call.

CES1 p.Ser280Phe

c.839C>T · VCV3491078

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7497 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7497	likely pathogenic
REVEL	0.362	indeterminate
SaProt	LLR -12.30	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP 1.5, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 17 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S279F vs ClinVar S280F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,892 alleles

Overall 0.000137% 2/1,461,838 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,892
Remaining individualsnot grpmax-eligible	0.0016%	62,504

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.Ser280Phe
Coding: c.839C>T
MANE Select: NM_001025195
Type: single nucleotide variant
Location: chr16:55819602 (GRCh38)
Gene constraint: LOEUF 1.272 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.27 · 21 PDB
Residue 280: a disulfide bond; an α-helix

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-ser280phe (accessed [today's date]).

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