Is CEL p.Arg540His (c.1619G>A) pathogenic?

CEL p.Arg540His (c.1619G>A) is classified Benign/Likely benign in CEL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2019-09-30). Low-frequency (popmax 1.63%, afr); Associated with monogenic diabetes.

What condition is associated with CEL p.Arg540His (c.1619G>A)?

CEL p.Arg540His (c.1619G>A) is associated with monogenic diabetes (ClinVar).

How common is CEL p.Arg540His (c.1619G>A) in the general population?

CEL p.Arg540His (c.1619G>A) is low-frequency (popmax 1.63%, afr) (gnomAD).

CEL p.Arg540His

c.1619G>A · rs201012268 · VCV393422

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.63%, afr)

Conditions

monogenic diabetes

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.161	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.79	GERP -2.7
Regional constraint	o/e 1.11	unconstrained · MANE · 642 bp · p 0.096 · regional, not allelic
Overall
CADD	9.67	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.63% African / African-American · 1,224/74,888 alleles

Filtering AF 1.56% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.53%

Overall 0.0897% 1,443/1,609,546 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.63%	61
Admixed American	0.14%	714
Remaining individualsnot grpmax-eligible	0.115%	867
Middle Eastern	0.0165%	6,060
South Asian	0.00659%	15,180
European (non-Finnish)	0.00466%	21,449
Finnishnot grpmax-eligible	0.00166%	60,094

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: CEL
Protein: p.Arg540His
Coding: c.1619G>A
MANE Select: NM_001807
dbSNP: rs201012268
Type: single nucleotide variant
Location: chr9:133071121 (GRCh38)
Gene constraint: LOEUF 0.972 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.10 · 7 PDB
Residue 540: an α-helix

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

Disease context

monogenic diabetes — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CEL p.Arg540Cys Likely benign ★ same residue
CEL p.Thr287Met Uncertain significance ★★ same condition
CEL p.Ile485Thr Benign/Likely benign ★★ same condition
CEL p.Leu118Arg Benign ★★ same condition
CEL p.Arg284Gly Conflicting classifications of pathogenicity ★ same condition
CEL p.Ile237Val Uncertain significance ★ same condition
CEL p.Val120Ile Conflicting classifications of pathogenicity ★ same condition
CEL c.67-3C>A 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/cel-p-arg540his (accessed [today's date]).

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