Is FADD p.Leu75= (c.223C>T) pathogenic?

FADD p.Leu75= (c.223C>T) is classified Likely benign in FADD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-29). Very rare (popmax 0.00866%, sas); Associated with FADD-related immunodeficiency.

What condition is associated with FADD p.Leu75= (c.223C>T)?

FADD p.Leu75= (c.223C>T) is associated with FADD-related immunodeficiency (ClinVar).

How common is FADD p.Leu75= (c.223C>T) in the general population?

FADD p.Leu75= (c.223C>T) is very rare (popmax 0.00866%, sas) (gnomAD).

How is FADD-related immunodeficiency inherited?

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

FADD p.Leu75=

c.223C>T · rs564798004 · VCV1923851

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00866%, sas)

Conditions

FADD-related immunodeficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.3	GERP 0.57, phastCons 1
Overall
CADD	13.63	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00866% South Asian · 7/80,864 alleles

Filtering AF 0.00399% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00281%

Overall 0.000659% 10/1,518,072 alleles · very rare exomes 7/1,365,896 · genomes 3/152,176 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00866%	11,552
Remaining individualsnot grpmax-eligible	0.00343%	29,174
Admixed American	0.00224%	44,574

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: FADD
Protein: p.Leu75=
Coding: c.223C>T
MANE Select: NM_003824
dbSNP: rs564798004
Type: single nucleotide variant
Location: chr11:70203682 (GRCh38)
Gene constraint: LOEUF 1.715 · pLI 0.07 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 72.60 · 18 PDB
Residue 75: the ded domain; an α-helix

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

Disease context

FADD-related immunodeficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For FADD-related immunodeficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

FADD p.Ala156Thr Uncertain significance ★★ same condition
FADD p.Asp106Asn Uncertain significance ★★ ⚠ same condition
FADD p.Ile126Met Uncertain significance ★★ ⚠ same condition
FADD p.Met193Thr Uncertain significance ★★ ⚠ same condition
FADD p.Ser18Arg Uncertain significance ★★ ⚠ same condition
FADD p.Thr151Ile Uncertain significance ★★ ⚠ same condition
FADD p.Val103Ile Uncertain significance ★★ ⚠ same condition
FADD c.286+20G>A Likely benign ★★ 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/fadd-p-leu75 (accessed [today's date]).

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