Is DIS3L2 p.Asp708= (c.2124C>T) pathogenic?

DIS3L2 p.Asp708= (c.2124C>T) is classified Conflicting classifications of pathogenicity in DIS3L2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-19). Ultra-rare (popmax 0.0272%, nfe); Associated with Perlman syndrome.

What condition is associated with DIS3L2 p.Asp708= (c.2124C>T)?

DIS3L2 p.Asp708= (c.2124C>T) is associated with Perlman syndrome (ClinVar).

How common is DIS3L2 p.Asp708= (c.2124C>T) in the general population?

DIS3L2 p.Asp708= (c.2124C>T) is ultra-rare (popmax 0.0272%, nfe) (gnomAD).

DIS3L2 p.Asp708=

c.2124C>T · rs368518323 · VCV241971

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0272%, nfe)

Conditions

Perlman syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.614	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.3	GERP -2.1
Overall
CADD	6.88	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0272% European (non-Finnish) · 321/1,179,802 alleles

Filtering AF 0.0247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0238%

Overall 0.0211% 340/1,612,544 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0272%	3,675
African / African-American	0.0107%	9,367
Remaining individualsnot grpmax-eligible	0.00961%	10,409
Admixed American	0.00333%	29,988
East Asian	0.00223%	44,882
South Asian	0.0022%	45,533

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.Asp708=
Coding: c.2124C>T
MANE Select: NM_152383
dbSNP: rs368518323
Type: single nucleotide variant
Location: chr2:232333953 (GRCh38)
Gene constraint: LOEUF 0.468 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 83.26 · 4 PDB
Residue 708: an α-helix

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.Asp708Asn Uncertain significance ★ ⚠ 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
DIS3L2 p.Glu332Ter 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-asp708 (accessed [today's date]).

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