Is LPL p.Arg137Trp (c.409C>T) pathogenic?

LPL p.Arg137Trp (c.409C>T) is classified Uncertain significance in LPL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-25). AlphaMissense: likely benign (0.1343); Ultra-rare (popmax 0.0329%, mid); Associated with Cardiovascular phenotype.

What condition is associated with LPL p.Arg137Trp (c.409C>T)?

LPL p.Arg137Trp (c.409C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is LPL p.Arg137Trp (c.409C>T) in the general population?

LPL p.Arg137Trp (c.409C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about LPL p.Arg137Trp (c.409C>T)?

AlphaMissense predicts likely benign (score 0.1343) — an in-silico prediction, not a clinical call.

LPL p.Arg137Trp

c.409C>T · rs376875031 · VCV3230721

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1343 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1343	likely benign
REVEL	0.444	indeterminate
SaProt	LLR -10.95	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP -2.1, phastCons 0.85
Regional constraint	o/e 1.09	unconstrained · MANE · 23 kb · p 0.027 · regional, not allelic
Overall
CADD	22.0	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 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.00105% 17/1,613,880 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
South Asian	0.00769%	13,010
Remaining individualsnot grpmax-eligible	0.0032%	31,240
African / African-American	0.00267%	37,424
East Asian	0.00223%	44,892
Admixed American	0.00167%	59,976
European (non-Finnish)	0.000169%	590,005

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.Arg137Trp
Coding: c.409C>T
MANE Select: NM_000237
dbSNP: rs376875031
Type: single nucleotide variant
Location: chr8:19951928 (GRCh38)
Gene constraint: LOEUF 1.075 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.36 · 5 PDB
Residue 137: an α-helix

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LPL p.Arg137Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
LPL c.1019-2A>T Pathogenic ★★ same condition
LPL c.1139+1G>A Likely pathogenic ★★ same condition
LPL c.1322+1G>C Pathogenic/Likely pathogenic ★★ same condition
LPL c.249+1G>A Pathogenic ★★ same condition
LPL p.Ala98Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
LPL p.Arg197Cys Likely pathogenic ★★ same condition
LPL p.Asp277Asn 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-arg137trp (accessed [today's date]).

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