Is LPL p.Arg116Trp (c.346C>T) pathogenic?

LPL p.Arg116Trp (c.346C>T) is classified Conflicting classifications of pathogenicity in LPL (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-24). AlphaMissense: ambiguous (0.5199); Very rare (popmax 0.00267%, afr); Associated with familial lipoprotein lipase deficiency.

What condition is associated with LPL p.Arg116Trp (c.346C>T)?

LPL p.Arg116Trp (c.346C>T) is associated with familial lipoprotein lipase deficiency (ClinVar).

How common is LPL p.Arg116Trp (c.346C>T) in the general population?

LPL p.Arg116Trp (c.346C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about LPL p.Arg116Trp (c.346C>T)?

AlphaMissense predicts ambiguous (score 0.5199) — an in-silico prediction, not a clinical call.

LPL p.Arg116Trp

c.346C>T · VCV4537244

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5199 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

familial lipoprotein lipase deficiency

Computational evidence

Protein change
AlphaMissense	0.5199	ambiguous
REVEL	0.676	pathogenic-leaning
SaProt	LLR -7.12	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.75	GERP -0.14, phastCons 0.18
Regional constraint	o/e 1.09	unconstrained · MANE · 23 kb · p 0.027 · regional, not allelic
Overall
CADD	21.7	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 0.00267% African / African-American · 2/74,892 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.00105% 17/1,613,974 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,243
African / African-Americangrpmax	0.00267%	37,446
Admixed American	0.00167%	59,988
Finnishnot grpmax-eligible	0.00156%	64,018
European (non-Finnish)	0.000932%	107,275

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg116Trp
Coding: c.346C>T
MANE Select: NM_000237
Type: single nucleotide variant
Location: chr8:19951865 (GRCh38)
Gene constraint: LOEUF 1.075 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.36 · 5 PDB
Residue 116: an α-helix

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.Arg116Gln Likely pathogenic ★ same residue
LPL p.Arg116Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
LPL p.Arg116= 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-arg116trp (accessed [today's date]).

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