Is CARD8 p.Phe199= (c.597C>T) pathogenic?

CARD8 p.Phe199= (c.597C>T) is classified Likely benign in CARD8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-10). Ultra-rare (popmax 0.0164%, mid).

How common is CARD8 p.Phe199= (c.597C>T) in the general population?

CARD8 p.Phe199= (c.597C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

CARD8 p.Phe199=

c.597C>T · VCV4690384

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

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 -0.048	GERP -2.8, phastCons 0.024
Overall
CADD	1.308	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00751% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00593%

Overall 0.000929% 15/1,614,058 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
South Asian	0.0132%	7,591
European (non-Finnish)	0.000169%	590,019

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.Phe199=
Coding: c.597C>T
MANE Select: NM_001184900
Type: single nucleotide variant
Location: chr19:48230952 (GRCh38)
Gene constraint: LOEUF 0.883 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.42 · 5 PDB
Residue 199: a UniProt-annotated variant site (in ibd30); the fiind domain; the 'zu5' region; a β-strand

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

Similar variants

CARD8 p.Phe199Leu 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
CARD8 p.Arg20Trp Uncertain significance ★★ same type
CARD8 p.Arg304Gln Uncertain significance ★★ same type
CARD8 p.Arg310Cys 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-phe199 (accessed [today's date]).

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