Is CEL p.Val593fs (c.1776del) pathogenic?

CEL p.Val593fs (c.1776del) is classified Likely pathogenic in CEL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2020-01-22). Ultra-rare (popmax 0.0109%, sas); Associated with maturity-onset diabetes of the young type 8.

What condition is associated with CEL p.Val593fs (c.1776del)?

CEL p.Val593fs (c.1776del) is associated with maturity-onset diabetes of the young type 8 (ClinVar).

How common is CEL p.Val593fs (c.1776del) in the general population?

CEL p.Val593fs (c.1776del) is ultra-rare (popmax 0.0109%, sas) (gnomAD).

How is MODY inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

CEL p.Val593fs

c.1776del · rs193922638 · VCV35815

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0109%, sas)

Conditions

maturity-onset diabetes of the young type 8

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (11 of 11) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1	GERP -1.6, phastCons 0.004
Overall
CADD	19.73	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	tandem	chr9:133080625 segmental duplication, simple repeat · ambiguous alignment · reads may not map uniquely · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0109% South Asian · 9/82,676 alleles

Filtering AF 0.00561% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00419%

Overall 0.000882% 12/1,361,032 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0109%	9,186
Ashkenazi Jewishnot grpmax-eligible	0.00358%	27,896
Finnishnot grpmax-eligible	0.0023%	43,482
Remaining individualsnot grpmax-eligible	0.0017%	58,662

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.Val593fs
Coding: c.1776del
MANE Select: NM_001807
dbSNP: rs193922638
Type: Deletion
Location: chr9:133071271 (GRCh38)
Gene constraint: LOEUF 0.972 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.10 · 7 PDB
Residue 593: the 'disordered' region; the '17 x 11 aa tandem repeats, glycodomain, o-linked (mucin type)' region

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

Disease context

maturity-onset diabetes of the young type 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For MODY (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

CEL p.Val626fs Likely pathogenic ★ same condition
CEL p.557ATPVPPTGDSE[1] Uncertain significance ★ same condition
CEL p.Ala601fs Conflicting classifications of pathogenicity ★ same condition
CEL p.Ala733_Lys743del Uncertain significance ★ same condition
CEL p.Asp719fs Uncertain significance ★ same condition
CEL p.Gly166fs Uncertain significance ★ same condition
CEL p.Gly721_Ser731del Uncertain significance ★ same condition
CEL p.Gly721_Ser742del Uncertain significance ★ same condition

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-val593fs (accessed [today's date]).

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