Is DIS3L2 p.Ala759Val (c.2276C>T) pathogenic?

DIS3L2 p.Ala759Val (c.2276C>T) is classified Uncertain significance in DIS3L2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-03-14). AlphaMissense: ambiguous (0.4142); Very rare (popmax 0.0022%, sas); Associated with Perlman syndrome.

What condition is associated with DIS3L2 p.Ala759Val (c.2276C>T)?

DIS3L2 p.Ala759Val (c.2276C>T) is associated with Perlman syndrome (ClinVar).

How common is DIS3L2 p.Ala759Val (c.2276C>T) in the general population?

DIS3L2 p.Ala759Val (c.2276C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about DIS3L2 p.Ala759Val (c.2276C>T)?

AlphaMissense predicts ambiguous (score 0.4142) — an in-silico prediction, not a clinical call.

DIS3L2 p.Ala759Val

c.2276C>T · rs1335621515 · VCV1011646

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4142 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Perlman syndrome

Computational evidence

Protein change
AlphaMissense	0.4142	ambiguous
REVEL	0.126	moderately benign-leaning
SaProt	LLR -11.84	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.31	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 5.9	GERP -0.18, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 2,680 bp · p 0.099 · regional, not allelic
Overall
CADD	25.0	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 0.0022% South Asian · 2/91,078 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000137% 2/1,461,534 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.Ala759Val
Coding: c.2276C>T
MANE Select: NM_152383
dbSNP: rs1335621515
Type: single nucleotide variant
Location: chr2:232334486 (GRCh38)
Gene constraint: LOEUF 0.468 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 83.26 · 4 PDB
Residue 759: 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.Ala759= 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
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-ala759val (accessed [today's date]).

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