Is FADD p.Pro3Arg (c.8C>G) pathogenic?

FADD p.Pro3Arg (c.8C>G) is classified Uncertain significance in FADD (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). AlphaMissense: likely benign (0.2045); Ultra-rare (popmax 0.0217%, sas); Associated with FADD-related immunodeficiency.

What condition is associated with FADD p.Pro3Arg (c.8C>G)?

FADD p.Pro3Arg (c.8C>G) is associated with FADD-related immunodeficiency (ClinVar).

How common is FADD p.Pro3Arg (c.8C>G) in the general population?

FADD p.Pro3Arg (c.8C>G) is ultra-rare (popmax 0.0217%, sas) (gnomAD).

How is FADD-related immunodeficiency inherited?

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

What do computational predictors say about FADD p.Pro3Arg (c.8C>G)?

AlphaMissense predicts likely benign (score 0.2045) — an in-silico prediction, not a clinical call.

FADD p.Pro3Arg

c.8C>G · rs763339860 · VCV1047817

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2045 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

FADD-related immunodeficiency

Computational evidence

Protein change
AlphaMissense	0.2045	likely benign
REVEL	0.302	indeterminate
SaProt	LLR -5.28	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -0.59, phastCons 0.036
Regional constraint	o/e 0.87	unconstrained · MANE · 3,010 bp · p 0.026 · regional, not allelic
Overall
CADD	19.29	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 0.0217% South Asian · 19/87,666 alleles

Filtering AF 0.0141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0118%

Overall 0.00139% 22/1,580,806 alleles · ultra-rare exomes 21/1,428,744 · genomes 1/152,062 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0217%	4,614
Remaining individualsnot grpmax-eligible	0.00163%	61,202
African / African-American	0.00135%	74,106
European (non-Finnish)	8.59e-05%	1,163,730

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.Pro3Arg
Coding: c.8C>G
MANE Select: NM_003824
dbSNP: rs763339860
Type: single nucleotide variant
Location: chr11:70203467 (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 3: 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.Pro3= Likely benign ★ same residue
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

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-pro3arg (accessed [today's date]).

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