Is DIS3L2 p.Pro514Ser (c.1540C>T) pathogenic?

DIS3L2 p.Pro514Ser (c.1540C>T) is classified Uncertain significance in DIS3L2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-10). AlphaMissense: ambiguous (0.3455); Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

What condition is associated with DIS3L2 p.Pro514Ser (c.1540C>T)?

DIS3L2 p.Pro514Ser (c.1540C>T) is associated with Inborn genetic diseases, Perlman syndrome (ClinVar).

How common is DIS3L2 p.Pro514Ser (c.1540C>T) in the general population?

DIS3L2 p.Pro514Ser (c.1540C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about DIS3L2 p.Pro514Ser (c.1540C>T)?

AlphaMissense predicts ambiguous (score 0.3455) — an in-silico prediction, not a clinical call.

DIS3L2 p.Pro514Ser

c.1540C>T · rs1463177673 · VCV463062

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3455 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3455	ambiguous
REVEL	0.245	benign-leaning
SaProt	LLR -12.53	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 319 kb · p 0.024 · regional, not allelic
Overall
CADD	25.5	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 0.00333% Admixed American · 2/60,024 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000205% 3/1,461,888 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,012
European (non-Finnish)	8.47e-05%	1,180,032

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.Pro514Ser
Coding: c.1540C>T
MANE Select: NM_152383
dbSNP: rs1463177673
Type: single nucleotide variant
Location: chr2:232263321 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Perlman syndrome

Similar variants

DIS3L2 p.Pro514Arg Uncertain significance ★ ⚠ same residue
DIS3L2 p.Pro514His Uncertain significance ★ ⚠ same residue
DIS3L2 p.Pro514= 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

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-pro514ser (accessed [today's date]).

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