Is LPL p.Arg197His (c.590G>A) pathogenic?

LPL p.Arg197His (c.590G>A) is classified Pathogenic/Likely pathogenic in LPL (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-01-07). AlphaMissense: likely benign (0.3048); Ultra-rare (popmax 0.025%, amr); Associated with hyperlipidemia, familial combined, LPL related.

What condition is associated with LPL p.Arg197His (c.590G>A)?

LPL p.Arg197His (c.590G>A) is associated with hyperlipidemia, familial combined, LPL related, familial lipoprotein lipase deficiency (ClinVar).

How common is LPL p.Arg197His (c.590G>A) in the general population?

LPL p.Arg197His (c.590G>A) is ultra-rare (popmax 0.025%, amr) (gnomAD).

What do computational predictors say about LPL p.Arg197His (c.590G>A)?

AlphaMissense predicts likely benign (score 0.3048) — an in-silico prediction, not a clinical call.

LPL p.Arg197His

c.590G>A · rs372668179 · VCV521082

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.3048 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.025%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hyperlipidemia, familial combined, LPL related

Computational evidence

Protein change
AlphaMissense	0.3048	likely benign ⚠ discordant with ClinVar
REVEL	0.618	indeterminate
SaProt	LLR -9.43	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	29.4	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 0.025% Admixed American · 15/59,992 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.00173% 28/1,614,002 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.025%	3,999
African / African-American	0.00401%	24,963
Finnishnot grpmax-eligible	0.00312%	32,014
South Asian	0.0011%	91,078
European (non-Finnish)	0.000593%	168,576

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.Arg197His
Coding: c.590G>A
MANE Select: NM_000237
dbSNP: rs372668179
Type: single nucleotide variant
Location: chr8:19954168 (GRCh38)
Gene constraint: LOEUF 1.075 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.36 · 5 PDB
Residue 197: a binding site

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

Disease context

hyperlipidemia, familial combined, LPL related — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial lipoprotein lipase deficiency

Similar variants

LPL p.Arg197Leu Pathogenic ★★ same residue
LPL p.Arg197Cys Likely pathogenic ★★ ⚠ same residue
LPL p.Arg197= Likely benign ★ 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

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-arg197his (accessed [today's date]).

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