Is LPL p.Val135= (c.405G>A) pathogenic?

LPL p.Val135= (c.405G>A) is classified Benign in LPL (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). Common (popmax 11.3%, afr) — too common for a highly-penetrant pathogenic allele; Associated with familial lipoprotein lipase deficiency.

What condition is associated with LPL p.Val135= (c.405G>A)?

LPL p.Val135= (c.405G>A) is associated with familial lipoprotein lipase deficiency (ClinVar).

LPL p.Val135=

Q: How common is LPL p.Val135= (c.405G>A) in the general population?

LPL p.Val135= (c.405G>A) is common (popmax 11.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.405G>A · rs1121923 · VCV362407

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Common

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

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 0.36	GERP -2.5, phastCons 0.97
Overall
CADD	5.975	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 11.3% African / African-American · 8,498/74,996 alleles

Filtering AF 11.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 11%

Overall 3.42% 55,135/1,614,046 alleles · common exomes 46,818/1,461,852 · genomes 8,317/152,194 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	11.3%	9
Ashkenazi Jewishnot grpmax-eligible	6.34%	16
Middle Eastern	6.3%	16
Amishnot grpmax-eligible	5.15%	19
Remaining individualsnot grpmax-eligible	3.7%	27
European (non-Finnish)	3.17%	32
Admixed American	3.02%	33
Finnishnot grpmax-eligible	2.79%	36
South Asian	1.06%	94

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.Val135=
Coding: c.405G>A
MANE Select: NM_000237
dbSNP: rs1121923
Type: single nucleotide variant
Location: chr8:19951924 (GRCh38)
Gene constraint: LOEUF 1.075 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.36 · 5 PDB
Residue 135: an α-helix

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-val135 (accessed [today's date]).

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