Is LIPC p.Val425Leu (c.1273G>C) pathogenic?

LIPC p.Val425Leu (c.1273G>C) is classified Uncertain significance in LIPC (ClinVar, Single submitter, 1 submitter; last evaluated 2017-04-27). AlphaMissense: likely benign (0.0982); Very rare (popmax 0.0011%, nfe); Associated with hyperlipidemia due to hepatic triglyceride lipase deficiency.

What condition is associated with LIPC p.Val425Leu (c.1273G>C)?

LIPC p.Val425Leu (c.1273G>C) is associated with hyperlipidemia due to hepatic triglyceride lipase deficiency (ClinVar).

How common is LIPC p.Val425Leu (c.1273G>C) in the general population?

LIPC p.Val425Leu (c.1273G>C) is very rare (popmax 0.0011%, nfe) (gnomAD).

What do computational predictors say about LIPC p.Val425Leu (c.1273G>C)?

AlphaMissense predicts likely benign (score 0.0982) — an in-silico prediction, not a clinical call.

LIPC p.Val425Leu

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.1273G>C · rs760387937 · VCV885172

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0982 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperlipidemia due to hepatic triglyceride lipase deficiency

Computational evidence

Protein change
AlphaMissense	0.0982	likely benign
REVEL	0.079	moderately benign-leaning
SaProt	LLR -5.47	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 3.9, phastCons 0.99
Regional constraint	o/e 1.08	unconstrained · MANE · 137 kb · p 0.056 · regional, not allelic
Overall
CADD	6.844	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 0.0011% European (non-Finnish) · 13/1,180,036 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000805% 13/1,614,222 alleles · very rare exomes 13/1,461,876 · genomes 0/152,346 · joint denominator

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.Val425Leu
Coding: c.1273G>C
MANE Select: NM_000236
dbSNP: rs760387937
Type: single nucleotide variant
Location: chr15:58563608 (GRCh38)
Gene constraint: LOEUF 1.102 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.03
Residue 425: the plat domain

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 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.Arg329His 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-val425leu (accessed [today's date]).

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