Is LPL p.Ile276Val (c.826A>G) pathogenic?

LPL p.Ile276Val (c.826A>G) is classified Uncertain significance in LPL (ClinVar, Single submitter, 1 submitter; last evaluated 2021-02-11). AlphaMissense: likely benign (0.2381); Very rare (popmax 8.47e-05%, nfe).

How common is LPL p.Ile276Val (c.826A>G) in the general population?

LPL p.Ile276Val (c.826A>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about LPL p.Ile276Val (c.826A>G)?

AlphaMissense predicts likely benign (score 0.2381) — an in-silico prediction, not a clinical call.

LPL p.Ile276Val

c.826A>G · VCV4899662

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2381 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2381	likely benign
REVEL	0.492	indeterminate
SaProt	LLR -8.21	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 9.4	GERP 2.7, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 23 kb · p 0.027 · regional, not allelic
Overall
CADD	22.7	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,024 alleles

Overall 6.84e-05% 1/1,461,880 alleles · very rare

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.Ile276Val
Coding: c.826A>G
MANE Select: NM_000237
Type: single nucleotide variant
Location: chr8:19955891 (GRCh38)
Gene constraint: LOEUF 1.075 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.36 · 5 PDB
Residue 276: an α-helix

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

Similar variants

LPL p.Ile276Thr Pathogenic ★ ⚠ same residue
LPL p.Ile276= 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-ile276val (accessed [today's date]).

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