Is LPL p.Ala98Ser (c.292G>T) pathogenic?

LPL p.Ala98Ser (c.292G>T) is classified Uncertain significance in LPL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-17). AlphaMissense: likely benign (0.2186); Absent from gnomAD v4.1.

How common is LPL p.Ala98Ser (c.292G>T) in the general population?

LPL p.Ala98Ser (c.292G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LPL p.Ala98Ser (c.292G>T)?

AlphaMissense predicts likely benign (score 0.2186) — an in-silico prediction, not a clinical call.

LPL p.Ala98Ser

c.292G>T · VCV4536636

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2186 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2186	likely benign
REVEL	0.586	indeterminate
SaProt	LLR -9.24	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 23 kb · p 0.027 · regional, not allelic
Overall
CADD	27.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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.Ala98Ser
Coding: c.292G>T
MANE Select: NM_000237
Type: single nucleotide variant
Location: chr8:19951811 (GRCh38)
Gene constraint: LOEUF 1.075 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.36 · 5 PDB
Residue 98: an α-helix; a UniProt-annotated variant site (in hlpp1; decreases the specific activity of the enzyme; reduces the secretion of the mutant protein significantly; the total lpl mass is reduced compared to that of the wild-type construct)

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

Similar variants

LPL p.Ala98Thr Pathogenic/Likely pathogenic ★★ ⚠ same residue
LPL p.Ala98= Likely benign ★ same residue
LPL c.1019-2A>T Pathogenic ★★ same type
LPL c.1019-3C>A Pathogenic/Likely pathogenic ★★ same type
LPL c.1139+1G>A Likely pathogenic ★★ same type
LPL c.1139+7A>G Likely pathogenic ★★ same type
LPL c.1322+1G>C Pathogenic/Likely pathogenic ★★ same type
LPL c.249+1G>A Pathogenic ★★ same type

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-ala98ser (accessed [today's date]).

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