Is DIS3L2 p.Arg608Pro (c.1823G>C) pathogenic?

DIS3L2 p.Arg608Pro (c.1823G>C) is classified Uncertain significance in DIS3L2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-28). AlphaMissense: likely pathogenic (0.9872); Absent from gnomAD v4.1; Associated with Perlman syndrome.

What condition is associated with DIS3L2 p.Arg608Pro (c.1823G>C)?

DIS3L2 p.Arg608Pro (c.1823G>C) is associated with Perlman syndrome (ClinVar).

How common is DIS3L2 p.Arg608Pro (c.1823G>C) in the general population?

DIS3L2 p.Arg608Pro (c.1823G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DIS3L2 p.Arg608Pro (c.1823G>C)?

AlphaMissense predicts likely pathogenic (score 0.9872) — an in-silico prediction, not a clinical call.

DIS3L2 p.Arg608Pro

c.1823G>C · rs2106348026 · VCV1389998

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9872 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Perlman syndrome

Computational evidence

Protein change
AlphaMissense	0.9872	likely pathogenic · top 5% in DIS3L2
REVEL	0.676	pathogenic-leaning
SaProt	LLR -16.11	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 1.5, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 319 kb · p 0.024 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DIS3L2
Protein: p.Arg608Pro
Coding: c.1823G>C
MANE Select: NM_152383
dbSNP: rs2106348026
Type: single nucleotide variant
Location: chr2:232329896 (GRCh38)
Gene constraint: LOEUF 0.468 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 83.26 · 4 PDB
Residue 608: 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 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
DIS3L2 p.Glu332Ter Likely pathogenic ★★ same condition
DIS3L2 p.Glu366Ter Pathogenic/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-arg608pro (accessed [today's date]).

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