Is CES1 p.Lys413Arg (c.1238A>G) pathogenic?

CES1 p.Lys413Arg (c.1238A>G) is classified Uncertain significance in CES1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-14). AlphaMissense: likely benign (0.0823); Ultra-rare (popmax 0.0329%, mid).

How common is CES1 p.Lys413Arg (c.1238A>G) in the general population?

CES1 p.Lys413Arg (c.1238A>G) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about CES1 p.Lys413Arg (c.1238A>G)?

AlphaMissense predicts likely benign (score 0.0823) — an in-silico prediction, not a clinical call.

CES1 p.Lys413Arg

c.1238A>G · rs776903994 · VCV3143218

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0823 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0823	likely benign
REVEL	0.028	moderately benign-leaning
SaProt	LLR -8.30	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 -3.8	GERP -1.8
Regional constraint	o/e 1.30	unconstrained · MANE · 17 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	12.79	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM K412R vs ClinVar K413R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.00919% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00735%

Overall 0.00607% 98/1,614,070 alleles · ultra-rare exomes 88/1,461,878 · genomes 10/152,192 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
South Asian	0.0154%	6,506
Remaining individualsnot grpmax-eligible	0.0112%	8,927
East Asian	0.0111%	8,981
European (non-Finnish)	0.00585%	17,102
Finnishnot grpmax-eligible	0.00156%	64,052

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.Lys413Arg
Coding: c.1238A>G
MANE Select: NM_001025195
dbSNP: rs776903994
Type: single nucleotide variant
Location: chr16:55810597 (GRCh38)
Gene constraint: LOEUF 1.272 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.27 · 21 PDB
Residue 412 UniProt numbering: 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-lys413arg (accessed [today's date]).

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