Is CASP10 p.Pro228Leu (c.683C>T) pathogenic?

CASP10 p.Pro228Leu (c.683C>T) is classified Conflicting classifications of pathogenicity in CASP10 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-15). AlphaMissense: likely benign (0.1238); Ultra-rare (popmax 0.0764%, nfe); Associated with autoimmune lymphoproliferative syndrome type 2A.

What condition is associated with CASP10 p.Pro228Leu (c.683C>T)?

CASP10 p.Pro228Leu (c.683C>T) is associated with autoimmune lymphoproliferative syndrome type 2A (ClinVar).

How common is CASP10 p.Pro228Leu (c.683C>T) in the general population?

CASP10 p.Pro228Leu (c.683C>T) is ultra-rare (popmax 0.0764%, nfe) (gnomAD).

How is Autoimmune lymphoproliferative syndrome inherited?

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

What do computational predictors say about CASP10 p.Pro228Leu (c.683C>T)?

AlphaMissense predicts likely benign (score 0.1238) — an in-silico prediction, not a clinical call.

CASP10 p.Pro228Leu

c.683C>T · rs143882052 · VCV535761

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1238 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0764%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autoimmune lymphoproliferative syndrome type 2A

Computational evidence

Protein change
AlphaMissense	0.1238	likely benign
REVEL	0.112	moderately benign-leaning
SaProt	LLR -6.41	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.9	GERP -1.3
Regional constraint	o/e 1.00	unconstrained · MANE · 32 kb · p 0.98 · regional, not allelic
Overall
CADD	12.14	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 0.0764% European (non-Finnish) · 897/1,173,434 alleles

Filtering AF 0.0722% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0706%

Overall 0.0578% 928/1,606,636 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0764%	1,308
Remaining individualsnot grpmax-eligible	0.0161%	6,223
East Asian	0.0156%	6,404
African / African-American	0.0107%	9,353
South Asian	0.0066%	15,157

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.Pro228Leu
Coding: c.683C>T
MANE Select: NM_032977
dbSNP: rs143882052
Type: single nucleotide variant
Location: chr2:201195947 (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.Pro228Ser 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-pro228leu (accessed [today's date]).

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