Is CARD8 p.Thr482fs (c.1440_1443dup) pathogenic?

CARD8 p.Thr482fs (c.14401443dup) is classified Uncertain significance in CARD8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-16). Very rare (popmax 0.000847%, nfe).

How common is CARD8 p.Thr482fs (c.1440_1443dup) in the general population?

CARD8 p.Thr482fs (c.1440_1443dup) is very rare (popmax 0.000847%, nfe) (gnomAD).

CARD8 p.Thr482fs

c.1440_1443dup · rs1269018291 · VCV1417439

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000847%, 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	escapes	premature termination codon in the last exon (14 of 14) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.003	GERP -0.14, phastCons 0.001

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000847% European (non-Finnish) · 10/1,180,000 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000821% 12/1,461,846 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00312%	32,019
European (non-Finnish)grpmax	0.000847%	118,000

Finnish 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: CARD8
Protein: p.Thr482fs
Coding: c.1440_1443dup
MANE Select: NM_001184900
dbSNP: rs1269018291
Type: Duplication
Location: chr19:48211880 (GRCh38)
Gene constraint: LOEUF 0.883 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.42 · 5 PDB
Residue 482: the card domain

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

Similar variants

CARD8 p.Thr482= Likely benign ★ same residue
CARD8 p.Glu5fs Uncertain significance ★★ same type
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

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-thr482fs (accessed [today's date]).

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