Is LPL p.Ser474Ter (c.1421C>G) pathogenic?

LPL p.Ser474Ter (c.1421C>G) is classified Benign/Likely benign in LPL (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-04). Common (popmax 12.1%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Cardiovascular phenotype.

What condition is associated with LPL p.Ser474Ter (c.1421C>G)?

LPL p.Ser474Ter (c.1421C>G) is associated with Cardiovascular phenotype, hyperlipidemia, familial combined, LPL related, familial lipoprotein lipase deficiency (ClinVar).

LPL p.Ser474Ter

Q: How common is LPL p.Ser474Ter (c.1421C>G) in the general population?

LPL p.Ser474Ter (c.1421C>G) is common (popmax 12.1%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1421C>G · rs328 · VCV1534

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Common

common (popmax 12.1%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (9 of 10, 6 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	Δ0.20	donor gain · deltas
Pangolin	Δ0.23	loss · gain 0.06 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP 4.9	GERP 2.4, phastCons 1
Overall
CADD	46.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 12.1% East Asian · 5,403/44,816 alleles

Filtering AF 11.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 11.7%

Overall 9.68% 156,015/1,611,322 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	15.5%	6
East Asiangrpmax	12.1%	8
Ashkenazi Jewishnot grpmax-eligible	10.6%	9
European (non-Finnish)	10%	10
South Asian	9.42%	11
Middle Eastern	9.23%	11
Remaining individualsnot grpmax-eligible	9.12%	11
Finnishnot grpmax-eligible	8.92%	11
African / African-American	6.84%	15
Admixed American	6.32%	16

Amish 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.Ser474Ter
Coding: c.1421C>G
MANE Select: NM_000237
dbSNP: rs328
Type: single nucleotide variant
Location: chr8:19962213 (GRCh38)
Gene constraint: LOEUF 1.075 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.36 · 5 PDB

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hyperlipidemia, familial combined, LPL related familial lipoprotein lipase deficiency

Similar variants

LPL p.Ser474= Likely benign ★ same residue
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.1322+1G>C Pathogenic/Likely pathogenic ★★ same condition
LPL c.249+1G>A Pathogenic ★★ same condition
LPL c.89-1G>A 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-ser474ter (accessed [today's date]).

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