Is LIPE p.Val1068fs (c.3203_3221del) pathogenic?

LIPE p.Val1068fs (c.32033221del) is classified Conflicting classifications of pathogenicity in LIPE (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-12-28). Rare (popmax 0.122%, mid); Associated with Lipodystrophy - childhood onset.

What condition is associated with LIPE p.Val1068fs (c.3203_3221del)?

LIPE p.Val1068fs (c.3203_3221del) is associated with Lipodystrophy - childhood onset, LIPE-related familial partial lipodystrophy (ClinVar).

How common is LIPE p.Val1068fs (c.3203_3221del) in the general population?

LIPE p.Val1068fs (c.3203_3221del) is rare (popmax 0.122%, mid) (gnomAD).

LIPE p.Val1068fs

c.3203_3221del · rs587777699 · VCV155901

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.122%, mid)

Conditions

Lipodystrophy - childhood onset

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (10 of 10) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.73
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	tandem	CCCCCGCAGCCCCCGTCTA simple repeat · ambiguous alignment · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.122% Middle Eastern · 5/4,098 alleles

Filtering AF 0.0521% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0469%

Overall 0.0477% 706/1,479,348 alleles · rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	2.42%	41
Ashkenazi Jewishnot grpmax-eligible	0.171%	585
Middle Easterngrpmax	0.122%	820
South Asian	0.0669%	1,494
European (non-Finnish)	0.0457%	2,187
Remaining individualsnot grpmax-eligible	0.0454%	2,201
Admixed American	0.0431%	2,319
African / African-American	0.0303%	3,297
East Asian	0.0285%	3,511

Amish 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: LIPE
Protein: p.Val1068fs
Coding: c.3203_3221del
MANE Select: NM_005357
dbSNP: rs587777699
Type: Deletion
Location: chr19:42401822 (GRCh38)
Gene constraint: LOEUF 0.932 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.77 · 1 PDB
Residue 1068: the 'disordered' region

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

Disease context

Lipodystrophy - childhood onset

Also linked: LIPE-related familial partial lipodystrophy

Similar variants

LIPE p.Leu913fs Uncertain significance ★★ same condition
LIPE p.Val1068Gly Likely benign ★ same residue
LIPE p.Arg305Cys Uncertain significance ★★ ⚠ same condition
LIPE p.Arg821Cys Uncertain significance ★★ ⚠ same condition
LIPE p.Leu1027Met Uncertain significance ★★ ⚠ same condition
LIPE p.Val1014Met Uncertain significance ★★ ⚠ same condition
LIPE p.Ala738fs Likely pathogenic ★ same condition
LIPE p.Arg374fs 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/lipe-p-val1068fs (accessed [today's date]).

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