Is CASP10 p.Arg109Pro (c.326G>C) pathogenic?

CASP10 p.Arg109Pro (c.326G>C) is classified Uncertain significance in CASP10 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-25). AlphaMissense: ambiguous (0.5371); Very rare (popmax 0.00017%, nfe); Associated with autoimmune lymphoproliferative syndrome type 2A.

What condition is associated with CASP10 p.Arg109Pro (c.326G>C)?

CASP10 p.Arg109Pro (c.326G>C) is associated with autoimmune lymphoproliferative syndrome type 2A (ClinVar).

How common is CASP10 p.Arg109Pro (c.326G>C) in the general population?

CASP10 p.Arg109Pro (c.326G>C) is very rare (popmax 0.00017%, 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.Arg109Pro (c.326G>C)?

AlphaMissense predicts ambiguous (score 0.5371) — an in-silico prediction, not a clinical call.

CASP10 p.Arg109Pro

c.326G>C · rs753330049 · VCV2162939

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5371 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

autoimmune lymphoproliferative syndrome type 2A

Computational evidence

Protein change
AlphaMissense	0.5371	ambiguous
REVEL	0.393	indeterminate
SaProt	LLR -11.74	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.5	GERP -3.3
Regional constraint	o/e 1.00	unconstrained · MANE · 32 kb · p 0.98 · regional, not allelic
Overall
CADD	2.46	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 0.00017% European (non-Finnish) · 2/1,179,870 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000206% 3/1,459,654 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,340
European (non-Finnish)grpmax	0.00017%	589,936

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg109Pro
Coding: c.326G>C
MANE Select: NM_032977
dbSNP: rs753330049
Type: single nucleotide variant
Location: chr2:201186103 (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.Arg109Ter 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-arg109pro (accessed [today's date]).

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