Is CARD8 p.Pro325Arg (c.974C>G) pathogenic?

CARD8 p.Pro325Arg (c.974C>G) is classified Benign in CARD8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-02). Common (popmax 13%, afr) — too common for a highly-penetrant pathogenic allele.

CARD8 p.Pro325Arg

Q: How common is CARD8 p.Pro325Arg (c.974C>G) in the general population?

CARD8 p.Pro325Arg (c.974C>G) is common (popmax 13%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.974C>G · rs73573000 · VCV1166618

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 13%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.082	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -2.8
Regional constraint	o/e 0.86	unconstrained · MANE · 29 kb · p 0.00022 · regional, not allelic
Overall
CADD	3.951	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 13% African / African-American · 9,758/74,962 alleles

Filtering AF 12.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.7%

Overall 0.897% 14,473/1,614,008 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	13%	8
Amishnot grpmax-eligible	6.15%	16
Middle Eastern	1.58%	63
Admixed American	1.31%	76
Remaining individualsnot grpmax-eligible	1.23%	81
South Asian	1.09%	91
Ashkenazi Jewishnot grpmax-eligible	0.78%	128
European (non-Finnish)	0.15%	667
East Asian	0.00891%	11,218
Finnishnot grpmax-eligible	0.00781%	12,807

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.Pro325Arg
Coding: c.974C>G
MANE Select: NM_001184900
dbSNP: rs73573000
Type: single nucleotide variant
Location: chr19:48230499 (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.Pro325Ala Uncertain significance ★ same residue
CARD8 p.Pro325Leu Uncertain significance ★ same residue
CARD8 p.Pro325= Likely benign ★ 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-pro325arg (accessed [today's date]).

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