Is DIS3L2 p.Phe782Leu (c.2346C>A) pathogenic?

DIS3L2 p.Phe782Leu (c.2346C>A) is classified Uncertain significance in DIS3L2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-14). AlphaMissense: likely pathogenic (0.9556); Very rare (popmax 0.00224%, eas); Associated with Perlman syndrome.

What condition is associated with DIS3L2 p.Phe782Leu (c.2346C>A)?

DIS3L2 p.Phe782Leu (c.2346C>A) is associated with Perlman syndrome (ClinVar).

How common is DIS3L2 p.Phe782Leu (c.2346C>A) in the general population?

DIS3L2 p.Phe782Leu (c.2346C>A) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about DIS3L2 p.Phe782Leu (c.2346C>A)?

AlphaMissense predicts likely pathogenic (score 0.9556) — an in-silico prediction, not a clinical call.

DIS3L2 p.Phe782Leu

c.2346C>A · rs375456340 · VCV1525472

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9556 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Perlman syndrome

Computational evidence

Protein change
AlphaMissense	0.9556	likely pathogenic
REVEL	0.257	benign-leaning
SaProt	LLR -11.40	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -8	GERP -1.8
Regional constraint	o/e 0.90	unconstrained · MANE · 2,680 bp · p 0.099 · regional, not allelic
Overall
CADD	15.98	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00224% East Asian · 1/44,692 alleles

Overall 6.21e-05% 1/1,610,820 alleles · very rare exomes 1/1,458,474 · 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: DIS3L2
Protein: p.Phe782Leu
Coding: c.2346C>A
MANE Select: NM_152383
dbSNP: rs375456340
Type: single nucleotide variant
Location: chr2:232334687 (GRCh38)
Gene constraint: LOEUF 0.468 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 83.26 · 4 PDB
Residue 782: 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.Phe782Val Uncertain significance ★ ⚠ same residue
DIS3L2 p.Phe782= Likely benign ★ same residue
DIS3L2 c.1740-1G>C Likely pathogenic ★★ same condition
DIS3L2 p.Arg245Ter Pathogenic/Likely pathogenic ★★ same condition
DIS3L2 p.Arg388Ter Pathogenic/Likely pathogenic ★★ same condition
DIS3L2 p.Arg43Ter Pathogenic/Likely pathogenic ★★ same condition
DIS3L2 p.Arg724Ter Pathogenic/Likely pathogenic ★★ same condition
DIS3L2 p.Gln604Ter 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-phe782leu (accessed [today's date]).

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