Is LPL p.Cys465Ser (c.1394G>C) pathogenic?

LPL p.Cys465Ser (c.1394G>C) is classified Uncertain significance in LPL (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-14). AlphaMissense: likely pathogenic (0.9819); Absent from gnomAD v4.1; Associated with familial lipoprotein lipase deficiency.

What condition is associated with LPL p.Cys465Ser (c.1394G>C)?

LPL p.Cys465Ser (c.1394G>C) is associated with familial lipoprotein lipase deficiency (ClinVar).

How common is LPL p.Cys465Ser (c.1394G>C) in the general population?

LPL p.Cys465Ser (c.1394G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LPL p.Cys465Ser (c.1394G>C)?

AlphaMissense predicts likely pathogenic (score 0.9819) — an in-silico prediction, not a clinical call.

LPL p.Cys465Ser

c.1394G>C · rs2128839829 · VCV1209597

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9819 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

familial lipoprotein lipase deficiency

Computational evidence

Protein change
AlphaMissense	0.9819	likely pathogenic
REVEL	0.621	indeterminate
SaProt	LLR -10.93	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 23 kb · p 0.027 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: LPL
Protein: p.Cys465Ser
Coding: c.1394G>C
MANE Select: NM_000237
dbSNP: rs2128839829
Type: single nucleotide variant
Location: chr8:19962186 (GRCh38)
Gene constraint: LOEUF 1.075 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.36 · 5 PDB
Residue 465: a β-strand; a disulfide bond; the 'interaction with gpihbp1' region

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 p.Cys465Tyr Uncertain significance ★ ⚠ 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.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-cys465ser (accessed [today's date]).

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