Is LIPC p.Arg329His (c.986G>A) pathogenic?

LIPC p.Arg329His (c.986G>A) is classified Uncertain significance in LIPC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-15). AlphaMissense: likely benign (0.0691); Ultra-rare (popmax 0.032%, afr); Associated with hyperlipidemia due to hepatic triglyceride lipase deficiency.

What condition is associated with LIPC p.Arg329His (c.986G>A)?

LIPC p.Arg329His (c.986G>A) is associated with hyperlipidemia due to hepatic triglyceride lipase deficiency (ClinVar).

How common is LIPC p.Arg329His (c.986G>A) in the general population?

LIPC p.Arg329His (c.986G>A) is ultra-rare (popmax 0.032%, afr) (gnomAD).

What do computational predictors say about LIPC p.Arg329His (c.986G>A)?

AlphaMissense predicts likely benign (score 0.0691) — an in-silico prediction, not a clinical call.

LIPC p.Arg329His

Q: How is Hyperlipidemia due to hepatic triacylglycerol lipase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.986G>A · rs149195239 · VCV886011

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0691 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.032%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hyperlipidemia due to hepatic triglyceride lipase deficiency

Computational evidence

Protein change
AlphaMissense	0.0691	likely benign
REVEL	0.338	indeterminate
SaProt	LLR -7.65	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 0.7	GERP 3.7, phastCons 0.98
Regional constraint	o/e 1.08	unconstrained · MANE · 137 kb · p 0.056 · regional, not allelic
Overall
CADD	19.75	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 0.032% African / African-American · 24/74,978 alleles

Filtering AF 0.022% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0195%

Overall 0.0195% 313/1,603,850 alleles · ultra-rare exomes 283/1,451,538 · genomes 30/152,312 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.032%	3,124
Remaining individualsnot grpmax-eligible	0.0306%	3,271
European (non-Finnish)	0.0226%	4,416
Middle Eastern	0.0167%	5,984
Admixed American	0.00173%	57,922
Finnishnot grpmax-eligible	0.00158%	63,216
South Asian	0.00111%	89,904

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: LIPC
Protein: p.Arg329His
Coding: c.986G>A
MANE Select: NM_000236
dbSNP: rs149195239
Type: single nucleotide variant
Location: chr15:58548507 (GRCh38)
Gene constraint: LOEUF 1.102 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.03

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

Disease context

hyperlipidemia due to hepatic triglyceride lipase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hyperlipidemia due to hepatic triacylglycerol lipase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: No data available

Similar variants

LIPC p.Arg329Cys Uncertain significance ★ ⚠ same residue
LIPC c.456+2T>C Uncertain significance ★★ same condition
LIPC c.456+5C>T Uncertain significance ★★ same condition
LIPC p.Ala105Val Uncertain significance ★★ ⚠ same condition
LIPC p.Ala106Val Uncertain significance ★★ ⚠ same condition
LIPC p.Arg135Cys Uncertain significance ★★ ⚠ same condition
LIPC p.Arg225Gln Uncertain significance ★★ ⚠ same condition
LIPC p.Arg333Gln Uncertain significance ★★ ⚠ 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/lipc-p-arg329his (accessed [today's date]).

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