Is CARD8 p.Val148fs (c.440_441dup) pathogenic?

CARD8 p.Val148fs (c.440441dup) is classified Benign in CARD8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-04). Common (popmax 9.43%, eas) — too common for a highly-penetrant pathogenic allele.

CARD8 p.Val148fs

Q: How common is CARD8 p.Val148fs (c.440_441dup) in the general population?

CARD8 p.Val148fs (c.440_441dup) is common (popmax 9.43%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.440_441dup · rs140826611 · VCV1170357

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Common

common (popmax 9.43%, eas) — 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.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 14
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.29	GERP -1.1, phastCons 0.003
Overall
CADD	17.32	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 9.43% East Asian · 4,232/44,868 alleles

Filtering AF 9.19% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1%

Overall 5.38% 86,849/1,613,752 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	9.43%	11
Finnishnot grpmax-eligible	6.09%	16
European (non-Finnish)	5.61%	18
South Asian	5.43%	18
Remaining individualsnot grpmax-eligible	5.39%	19
Ashkenazi Jewishnot grpmax-eligible	4.65%	22
Middle Eastern	3.7%	27
Admixed American	3.26%	31
African / African-American	0.896%	112
Amishnot grpmax-eligible	0.11%	912

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.Val148fs
Coding: c.440_441dup
MANE Select: NM_001184900
dbSNP: rs140826611
Type: Duplication
Location: chr19:48231760 (GRCh38)
Gene constraint: LOEUF 0.883 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.42 · 5 PDB
Residue 148: a UniProt-annotated variant site (in ibd30)

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

Similar variants

CARD8 p.Glu5fs Uncertain significance ★★ 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-val148fs (accessed [today's date]).

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