Is CARD8 p.Glu5fs (c.11dup) pathogenic?

CARD8 p.Glu5fs (c.11dup) is classified Uncertain significance in CARD8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-14). Ultra-rare (popmax 0.0382%, nfe).

How common is CARD8 p.Glu5fs (c.11dup) in the general population?

CARD8 p.Glu5fs (c.11dup) is ultra-rare (popmax 0.0382%, nfe) (gnomAD).

CARD8 p.Glu5fs

c.11dup · rs759553123 · VCV1008662

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0382%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 14
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.47	GERP -0.81
Overall
CADD	16.11	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0382% European (non-Finnish) · 438/1,146,638 alleles

Filtering AF 0.0352% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0341%

Overall 0.0301% 462/1,535,770 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0382%	2,618
Admixed American	0.0216%	4,633
Remaining individualsnot grpmax-eligible	0.0117%	8,569
Ashkenazi Jewishnot grpmax-eligible	0.00698%	14,324
Finnishnot grpmax-eligible	0.0045%	22,245
African / African-American	0.00274%	36,510

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.Glu5fs
Coding: c.11dup
MANE Select: NM_001184900
dbSNP: rs759553123
Type: Duplication
Location: chr19:48241009 (GRCh38)
Gene constraint: LOEUF 0.883 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.42 · 5 PDB
Residue 5: the 'disordered' region

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

Similar variants

CARD8 p.Val148fs Benign ★★ same type
CARD8 c.1348+2dup Uncertain significance ★ same type
CARD8 p.Asp114fs Uncertain significance ★ same type
CARD8 p.Gln61fs Conflicting classifications of pathogenicity ★ same type
CARD8 p.Gln90fs Uncertain significance ★ same type
CARD8 p.Ser130fs Uncertain significance ★ same type
CARD8 p.Thr482fs Uncertain significance ★ same type
CARD8 p.Tyr180fs 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-glu5fs (accessed [today's date]).

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