Is DIS3L2 p.Leu768fs (c.2302del) pathogenic?

DIS3L2 p.Leu768fs (c.2302del) is classified Pathogenic/Likely pathogenic in DIS3L2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-03). Very rare (popmax 0.00225%, eas); Associated with Perlman syndrome.

What condition is associated with DIS3L2 p.Leu768fs (c.2302del)?

DIS3L2 p.Leu768fs (c.2302del) is associated with Perlman syndrome (ClinVar).

How common is DIS3L2 p.Leu768fs (c.2302del) in the general population?

DIS3L2 p.Leu768fs (c.2302del) is very rare (popmax 0.00225%, eas) (gnomAD).

DIS3L2 p.Leu768fs

c.2302del · rs1559220022 · VCV2674842

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00225%, eas)

Conditions

Perlman syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 19 of 21
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 0.9, phastCons 1
Region caveats
Repeat context	seg dup	· reads may not map uniquely · confidence, not pathogenicity

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00225% East Asian · 1/44,406 alleles

Overall 6.87e-05% 1/1,455,366 alleles · very rare

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: DIS3L2
Protein: p.Leu768fs
Coding: c.2302del
MANE Select: NM_152383
dbSNP: rs1559220022
Type: Deletion
Location: chr2:232334639 (GRCh38)
Gene constraint: LOEUF 0.468 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 83.26 · 4 PDB
Residue 768: a β-strand

Full DIS3L2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Perlman syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DIS3L2 p.Arg17fs Pathogenic/Likely pathogenic ★★ same condition
DIS3L2 p.Asn740fs Pathogenic ★★ same condition
DIS3L2 p.Cys216fs Pathogenic/Likely pathogenic ★★ same condition
DIS3L2 p.Thr662fs Pathogenic/Likely pathogenic ★★ same condition
DIS3L2 p.Lys870del Uncertain significance ★★ same condition
DIS3L2 c.211-9del Likely benign ★★ same condition
DIS3L2 c.602-19_602-16del Likely benign ★★ same condition
DIS3L2 c.1318-11_1318-2del 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/dis3l2-p-leu768fs (accessed [today's date]).

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