Is DIS3L2 p.Ala549fs (c.1644dup) pathogenic?

DIS3L2 p.Ala549fs (c.1644dup) is classified Uncertain significance in DIS3L2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-06). Very rare (popmax 8.69e-05%, nfe); Associated with Perlman syndrome.

What condition is associated with DIS3L2 p.Ala549fs (c.1644dup)?

DIS3L2 p.Ala549fs (c.1644dup) is associated with Perlman syndrome (ClinVar).

How common is DIS3L2 p.Ala549fs (c.1644dup) in the general population?

DIS3L2 p.Ala549fs (c.1644dup) is very rare (popmax 8.69e-05%, nfe) (gnomAD).

DIS3L2 p.Ala549fs

c.1644dup · VCV3893096

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.69e-05%, nfe)

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-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.3	GERP -0.3, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.69e-05% European (non-Finnish) · 1/1,150,380 alleles

Overall 7.12e-05% 1/1,404,490 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.Ala549fs
Coding: c.1644dup
MANE Select: NM_152383 · reported on NM_001257281
Type: Duplication
Location: chr2:232343406 (GRCh38)
Gene constraint: LOEUF 0.468 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 83.26 · 4 PDB

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.Asp109fs Pathogenic/Likely pathogenic ★★ same condition
DIS3L2 p.Cys303fs Pathogenic ★ same condition
DIS3L2 p.Ile181fs Pathogenic ★ same condition
DIS3L2 p.Ile516fs Pathogenic ★ same condition
DIS3L2 p.Ile597fs Pathogenic ★ same condition
DIS3L2 p.Ile96fs Pathogenic ★ same condition
DIS3L2 p.Leu267fs Pathogenic ★ same condition
DIS3L2 p.Met443fs 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-ala549fs (accessed [today's date]).

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