Is CEL p.Pro678Ala (c.2032C>G) pathogenic?

CEL p.Pro678Ala (c.2032C>G) is classified Likely benign in CEL (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-02-16). Ultra-rare (popmax 0.0506%, mid).

How common is CEL p.Pro678Ala (c.2032C>G) in the general population?

CEL p.Pro678Ala (c.2032C>G) is ultra-rare (popmax 0.0506%, mid) (gnomAD).

CEL p.Pro678Ala

c.2032C>G · rs490954 · VCV1328317

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0506%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.099	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2	GERP -0.066
Regional constraint	o/e 1.11	unconstrained · MANE · 642 bp · p 0.096 · regional, not allelic
Overall
CADD	0.28	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0506% Middle Eastern · 1/1,976 alleles

Filtering AF 0.0411% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0391%

Overall 0.05% 337/673,422 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.282%	355
Amishnot grpmax-eligible	0.237%	422
Ashkenazi Jewishnot grpmax-eligible	0.0771%	1,297
Remaining individualsnot grpmax-eligible	0.0713%	1,402
Middle Easterngrpmax	0.0506%	1,976
European (non-Finnish)	0.046%	2,175
South Asian	0.0324%	3,083
African / African-American	0.0239%	4,180
Admixed American	0.0192%	5,206
East Asian	0.0118%	8,465

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro678Ala
Coding: c.2032C>G
MANE Select: NM_001807
dbSNP: rs490954
Type: single nucleotide variant
Location: chr9:133071534 (GRCh38)
Gene constraint: LOEUF 0.972 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.10 · 7 PDB
Residue 678: 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

Similar variants

CEL p.Pro678fs Likely benign ★ same residue
CEL c.67-3C>A Uncertain significance ★★ same type
CEL p.Ala295Ser Uncertain significance ★★ same type
CEL p.Ala548Glu Uncertain significance ★★ same type
CEL p.Ala722Val Uncertain significance ★★ same type
CEL p.Arg116Gln Uncertain significance ★★ same type
CEL p.Arg185Trp Uncertain significance ★★ same type
CEL p.Arg443Trp 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-pro678ala (accessed [today's date]).

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