Is LPL p.Ile252Thr (c.755T>C) pathogenic?

LPL p.Ile252Thr (c.755T>C) is classified Pathogenic/Likely pathogenic in LPL (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-12-09). AlphaMissense: likely pathogenic (0.8052); Very rare (popmax 0.00492%, nfe); Associated with LPL-related disorder.

What condition is associated with LPL p.Ile252Thr (c.755T>C)?

LPL p.Ile252Thr (c.755T>C) is associated with LPL-related disorder, hyperlipidemia, familial combined, LPL related, familial lipoprotein lipase deficiency (ClinVar).

How common is LPL p.Ile252Thr (c.755T>C) in the general population?

LPL p.Ile252Thr (c.755T>C) is very rare (popmax 0.00492%, nfe) (gnomAD).

What do computational predictors say about LPL p.Ile252Thr (c.755T>C)?

AlphaMissense predicts likely pathogenic (score 0.8052) — an in-silico prediction, not a clinical call.

LPL p.Ile252Thr

c.755T>C · rs118204080 · VCV1554

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.8052 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00492%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

LPL-related disorder

Computational evidence

Protein change
AlphaMissense	0.8052	likely pathogenic ✓ concordant with ClinVar
REVEL	0.726	pathogenic-leaning
SaProt	LLR -7.81	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.8, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 23 kb · p 0.027 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00492% European (non-Finnish) · 58/1,179,914 alleles

Filtering AF 0.00386% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00353%

Overall 0.00417% 61/1,461,744 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00492%	20,343
South Asian	0.0022%	45,543
Remaining individualsnot grpmax-eligible	0.0016%	62,504

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.Ile252Thr
Coding: c.755T>C
MANE Select: NM_000237
dbSNP: rs118204080
Type: single nucleotide variant
Location: chr8:19954333 (GRCh38)
Gene constraint: LOEUF 1.075 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.36 · 5 PDB
Residue 252: an α-helix; a disulfide bond; the 'essential for determining substrate specificity' region; a UniProt-annotated variant site (in hlpp1)

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

Disease context

LPL-related disorder

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

Similar variants

LPL p.Ile252Met 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-ile252thr (accessed [today's date]).

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