Is LPL p.Ser63= (c.189C>T) pathogenic?

LPL p.Ser63= (c.189C>T) is classified Conflicting classifications of pathogenicity in LPL (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-12). Ultra-rare (popmax 0.02%, nfe); Associated with familial lipoprotein lipase deficiency.

What condition is associated with LPL p.Ser63= (c.189C>T)?

LPL p.Ser63= (c.189C>T) is associated with familial lipoprotein lipase deficiency (ClinVar).

How common is LPL p.Ser63= (c.189C>T) in the general population?

LPL p.Ser63= (c.189C>T) is ultra-rare (popmax 0.02%, nfe) (gnomAD).

LPL p.Ser63=

c.189C>T · rs114726797 · VCV764668

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, nfe)

Conditions

familial lipoprotein lipase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.6	GERP -5.2
Overall
CADD	1.989	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.02% European (non-Finnish) · 236/1,180,010 alleles

Filtering AF 0.0179% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0171%

Overall 0.0177% 286/1,614,090 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0642%	1,558
European (non-Finnish)grpmax	0.02%	5,000
African / African-American	0.016%	6,251
Finnishnot grpmax-eligible	0.0141%	7,116
Remaining individualsnot grpmax-eligible	0.0096%	10,418
East Asian	0.00669%	14,955
South Asian	0.0011%	91,070

Ashkenazi Jewish 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: LPL
Protein: p.Ser63=
Coding: c.189C>T
MANE Select: NM_000237
dbSNP: rs114726797
Type: single nucleotide variant
Location: chr8:19948280 (GRCh38)
Gene constraint: LOEUF 1.075 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.36 · 5 PDB
Residue 63: an α-helix; a disulfide bond

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

Disease context

familial lipoprotein lipase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LPL c.1019-2A>T Pathogenic ★★ same condition
LPL c.1019-3C>A Pathogenic/Likely pathogenic ★★ same condition
LPL c.1139+1G>A Likely pathogenic ★★ same condition
LPL c.1139+7A>G Likely pathogenic ★★ same condition
LPL c.249+1G>A Pathogenic ★★ same condition
LPL c.89-1G>A Pathogenic/Likely pathogenic ★★ same condition
LPL c.89-1G>C Pathogenic/Likely pathogenic ★★ same condition
LPL p.Ala98Thr Pathogenic/Likely pathogenic ★★ ⚠ 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/lpl-p-ser63 (accessed [today's date]).

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