Is CARD8 p.Pro325= (c.975C>T) pathogenic?

CARD8 p.Pro325= (c.975C>T) is classified Likely benign in CARD8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-13). Very rare (popmax 0.000169%, nfe).

How common is CARD8 p.Pro325= (c.975C>T) in the general population?

CARD8 p.Pro325= (c.975C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

CARD8 p.Pro325=

c.975C>T · VCV4798084

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.48	GERP -2.8
Overall
CADD	1.827	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,966 alleles

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

Overall 0.000137% 2/1,461,796 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: CARD8
Protein: p.Pro325=
Coding: c.975C>T
MANE Select: NM_001184900
Type: single nucleotide variant
Location: chr19:48230498 (GRCh38)
Gene constraint: LOEUF 0.883 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.42 · 5 PDB
Residue 325: a UniProt-annotated variant site (in ibd30); the fiind domain; the 'upa' region

Full CARD8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CARD8 p.Pro325Thr Uncertain significance ★★ same residue
CARD8 p.Pro325Arg Benign ★★ same residue
CARD8 p.Pro325Ala Uncertain significance ★ same residue
CARD8 p.Pro325Leu Uncertain significance ★ same residue
CARD8 c.1035+5G>A Uncertain significance ★★ same type
CARD8 p.Ala442Pro Uncertain significance ★★ same type
CARD8 p.Ala97Val Uncertain significance ★★ same type
CARD8 p.Arg103His Uncertain significance ★★ same type

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/card8-p-pro325 (accessed [today's date]).

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