Is LPL p.Thr83= (c.249G>A) pathogenic?

LPL p.Thr83= (c.249G>A) is classified Uncertain significance in LPL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-01). Ultra-rare (popmax 0.0527%, sas); Associated with familial lipoprotein lipase deficiency.

What condition is associated with LPL p.Thr83= (c.249G>A)?

LPL p.Thr83= (c.249G>A) is associated with familial lipoprotein lipase deficiency (ClinVar).

How common is LPL p.Thr83= (c.249G>A) in the general population?

LPL p.Thr83= (c.249G>A) is ultra-rare (popmax 0.0527%, sas) (gnomAD).

LPL p.Thr83=

c.249G>A · rs544872445 · VCV908635

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0527%, sas)

Conditions

familial lipoprotein lipase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.25 · evaluated, not missing
Pangolin	Δ0.21	loss · gain 0.06 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 1.8	GERP -0.37, phastCons 1
Overall
CADD	18.34	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0527% South Asian · 48/91,048 alleles

Filtering AF 0.0408% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0366%

Overall 0.0039% 63/1,613,716 alleles · ultra-rare exomes 57/1,461,470 · genomes 6/152,246 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0527%	1,897
Remaining individualsnot grpmax-eligible	0.0048%	20,826
African / African-American	0.004%	25,005
East Asian	0.00223%	44,860
European (non-Finnish)	0.000678%	147,463

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.Thr83=
Coding: c.249G>A
MANE Select: NM_000237
dbSNP: rs544872445
Type: single nucleotide variant
Location: chr8:19948340 (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

familial lipoprotein lipase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LPL p.Thr83Met 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-thr83 (accessed [today's date]).

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