Is CASP10 p.Leu520Phe (c.1558C>T) pathogenic?

CASP10 p.Leu520Phe (c.1558C>T) is classified Uncertain significance in CASP10 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-20). Ultra-rare (popmax 0.012%, afr); Associated with autoimmune lymphoproliferative syndrome type 2A.

What condition is associated with CASP10 p.Leu520Phe (c.1558C>T)?

CASP10 p.Leu520Phe (c.1558C>T) is associated with autoimmune lymphoproliferative syndrome type 2A (ClinVar).

How common is CASP10 p.Leu520Phe (c.1558C>T) in the general population?

CASP10 p.Leu520Phe (c.1558C>T) is ultra-rare (popmax 0.012%, afr) (gnomAD).

How is Autoimmune lymphoproliferative syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

CASP10 p.Leu520Phe

c.1558C>T · rs571838418 · VCV1018382

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Conditions

autoimmune lymphoproliferative syndrome type 2A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.018	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.55	GERP -3.5
Regional constraint	o/e 1.00	unconstrained · MANE · 32 kb · p 0.98 · regional, not allelic
Overall
CADD	1.182	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.012% African / African-American · 9/75,008 alleles

Filtering AF 0.00623% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00467%

Overall 0.000682% 11/1,614,000 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,334
Admixed American	0.00167%	60,008
Remaining individualsnot grpmax-eligible	0.0016%	62,498

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: CASP10
Protein: p.Leu520Phe
Coding: c.1558C>T
MANE Select: NM_032977
dbSNP: rs571838418
Type: single nucleotide variant
Location: chr2:201217730 (GRCh38)
Gene constraint: LOEUF 1.046 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 69.54

Full CASP10 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autoimmune lymphoproliferative syndrome type 2A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autoimmune lymphoproliferative syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages

Similar variants

CASP10 p.Leu520Val Uncertain significance ★ same residue
CASP10 c.1415+2T>C Uncertain significance ★★ same condition
CASP10 c.1416-3C>A Uncertain significance ★★ same condition
CASP10 c.347+2T>G Uncertain significance ★★ same condition
CASP10 c.684+1G>A Uncertain significance ★★ same condition
CASP10 c.922+5G>A Uncertain significance ★★ same condition
CASP10 p.Ala237Glu Uncertain significance ★★ ⚠ same condition
CASP10 p.Ala248Val Uncertain significance ★★ ⚠ 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/casp10-p-leu520phe (accessed [today's date]).

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