Is CARD11 p.Ser439Phe (c.1316C>T) pathogenic?

CARD11 p.Ser439Phe (c.1316C>T) is classified Uncertain significance in CARD11 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-09-27). AlphaMissense: likely benign (0.2228); Ultra-rare (popmax 0.0165%, mid); Associated with severe combined immunodeficiency due to CARD11 deficiency.

What condition is associated with CARD11 p.Ser439Phe (c.1316C>T)?

CARD11 p.Ser439Phe (c.1316C>T) is associated with severe combined immunodeficiency due to CARD11 deficiency, BENTA disease (ClinVar).

How common is CARD11 p.Ser439Phe (c.1316C>T) in the general population?

CARD11 p.Ser439Phe (c.1316C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CARD11 p.Ser439Phe (c.1316C>T)?

AlphaMissense predicts likely benign (score 0.2228) — an in-silico prediction, not a clinical call.

CARD11 p.Ser439Phe

Q: How is Combined immunodeficiency due to CARD11 deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1316C>T · rs760856731 · VCV569943

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2228 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

severe combined immunodeficiency due to CARD11 deficiency

Computational evidence

Protein change
AlphaMissense	0.2228	likely benign
REVEL	0.184	benign-leaning
SaProt	LLR -9.46	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.5	GERP 2.2, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 31 kb · p 2.9e-06 · regional, not allelic
Overall
CADD	26.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000958% 14/1,461,726 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0016%	62,508
South Asian	0.0011%	91,082
European (non-Finnish)	0.000932%	107,274

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: CARD11
Protein: p.Ser439Phe
Coding: c.1316C>T
MANE Select: NM_032415
dbSNP: rs760856731
Type: single nucleotide variant
Location: chr7:2937062 (GRCh38)
Gene constraint: LOEUF 0.364 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.83 · 2 PDB

Full CARD11 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

severe combined immunodeficiency due to CARD11 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: BENTA disease

For Combined immunodeficiency due to CARD11 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

CARD11 p.Ser439Cys Uncertain significance ★ ⚠ same residue
CARD11 p.Arg30Trp Pathogenic/Likely pathogenic ★★ same condition
CARD11 p.Arg47His Pathogenic/Likely pathogenic ★★ same condition
CARD11 p.Arg837Ter Pathogenic ★★ same condition
CARD11 p.Gly123Asp Pathogenic ★★ ⚠ same condition
CARD11 p.Gly123Ser Pathogenic ★★ ⚠ same condition
CARD11 c.1807+5G>A Uncertain significance ★★ same condition
CARD11 c.2269+3G>A Uncertain significance ★★ same condition

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/card11-p-ser439phe (accessed [today's date]).

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