Is CARD18 p.Leu76Phe (c.226C>T) pathogenic?

CARD18 p.Leu76Phe (c.226C>T) is classified Uncertain significance in CARD18 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-07). AlphaMissense: likely benign (0.2948); Very rare (popmax 0.00329%, sas).

How common is CARD18 p.Leu76Phe (c.226C>T) in the general population?

CARD18 p.Leu76Phe (c.226C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about CARD18 p.Leu76Phe (c.226C>T)?

AlphaMissense predicts likely benign (score 0.2948) — an in-silico prediction, not a clinical call.

CARD18 p.Leu76Phe

c.226C>T · rs1339729041 · VCV2481758

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2948 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2948	likely benign
REVEL	0.262	benign-leaning
SaProt	LLR -10.22	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.3
Regional constraint	o/e 1.27	unconstrained · MANE · 910 bp · p 0.0055 · regional, not allelic
Overall
CADD	1.464	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,084 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000205% 3/1,461,372 alleles · very rare

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: CARD18
Protein: p.Leu76Phe
Coding: c.226C>T
MANE Select: NM_021571
dbSNP: rs1339729041
Type: single nucleotide variant
Location: chr11:105138860 (GRCh38)
Gene constraint: LOEUF 1.545 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.56 · 1 PDB
Residue 76: the card domain; an α-helix

Full CARD18 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CARD18 p.Ala19Ser Uncertain significance ★ ⚠ same type
CARD18 p.Ala2Val Uncertain significance ★ ⚠ same type
CARD18 p.Ala54Ser Uncertain significance ★ ⚠ same type
CARD18 p.Arg10Gly Uncertain significance ★ ⚠ same type
CARD18 p.Ile35Thr Uncertain significance ★ ⚠ same type
CARD18 p.Leu26Pro Uncertain significance ★ ⚠ same type
CARD18 p.Leu30Ile Uncertain significance ★ ⚠ same type
CARD18 p.Leu60Phe 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/card18-p-leu76phe (accessed [today's date]).

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