Is LPL p.Pro226= (c.678A>G) pathogenic?

LPL p.Pro226= (c.678A>G) is classified Benign/Likely benign in LPL (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-02). Low-frequency (popmax 1.63%, sas); Associated with Cardiovascular phenotype.

What condition is associated with LPL p.Pro226= (c.678A>G)?

LPL p.Pro226= (c.678A>G) is associated with Cardiovascular phenotype, familial lipoprotein lipase deficiency (ClinVar).

How common is LPL p.Pro226= (c.678A>G) in the general population?

LPL p.Pro226= (c.678A>G) is low-frequency (popmax 1.63%, sas) (gnomAD).

LPL p.Pro226=

c.678A>G · rs558390128 · VCV362411

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.63%, sas)

Conditions

Cardiovascular phenotype

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 0.59	GERP -2.1, phastCons 0.86
Overall
CADD	8.083	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.63% South Asian · 1,489/91,084 alleles

Filtering AF 1.57% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.54%

Overall 0.0963% 1,554/1,614,196 alleles · low-frequency exomes 1,481/1,461,886 · genomes 73/152,310 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	1.63%	61
Remaining individualsnot grpmax-eligible	0.0864%	1,158
Middle Eastern	0.0165%	6,062
African / African-American	0.004%	25,014
East Asian	0.00223%	44,882
Admixed American	0.00167%	60,018
European (non-Finnish)	0.000424%	236,007

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.Pro226=
Coding: c.678A>G
MANE Select: NM_000237
dbSNP: rs558390128
Type: single nucleotide variant
Location: chr8:19954256 (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: familial lipoprotein lipase deficiency

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.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
LPL c.89-1G>C 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-pro226 (accessed [today's date]).

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