Is CEL p.Ser621Ala (c.1861T>G) pathogenic?

CEL p.Ser621Ala (c.1861T>G) is classified Conflicting classifications of pathogenicity in CEL (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-02-25). Common (popmax 11.3%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Inborn genetic diseases.

What condition is associated with CEL p.Ser621Ala (c.1861T>G)?

CEL p.Ser621Ala (c.1861T>G) is associated with Inborn genetic diseases (ClinVar).

CEL p.Ser621Ala

Q: How common is CEL p.Ser621Ala (c.1861T>G) in the general population?

CEL p.Ser621Ala (c.1861T>G) is common (popmax 11.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1861T>G · VCV3831273

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 11.3%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

Inborn genetic diseases

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 -3	GERP 0.5
Regional constraint	o/e 1.11	unconstrained · MANE · 642 bp · p 0.096 · regional, not allelic
Overall
CADD	12.92	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 11.3% African / African-American · 39/344 alleles

Filtering AF 8.53% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.55%

Overall 0.513% 109/21,234 alleles · common exomes 101/21,128 · genomes 8/106 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	11.3%	9
Remaining individualsnot grpmax-eligible	1.07%	94
Ashkenazi Jewishnot grpmax-eligible	0.923%	108
South Asian	0.753%	133
Admixed American	0.704%	142
Finnishnot grpmax-eligible	0.282%	354
European (non-Finnish)	0.232%	431

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.Ser621Ala
Coding: c.1861T>G
MANE Select: NM_001807
Type: single nucleotide variant
Location: chr9:133071363 (GRCh38)
Gene constraint: LOEUF 0.972 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.10 · 7 PDB
Residue 621: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CEL p.Ala295Ser Uncertain significance ★★ same condition
CEL p.Ala548Glu Uncertain significance ★★ same condition
CEL p.Arg185Trp Uncertain significance ★★ same condition
CEL p.Arg443Trp Uncertain significance ★★ same condition
CEL p.Gln460Arg Uncertain significance ★★ same condition
CEL p.Glu710Lys Uncertain significance ★★ same condition
CEL p.Gly147Ser Uncertain significance ★★ same condition
CEL p.His68Leu 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-ser621ala (accessed [today's date]).

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