Is AICDA p.Arg8Trp (c.22C>T) pathogenic?

AICDA p.Arg8Trp (c.22C>T) is classified Uncertain significance in AICDA (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-03). AlphaMissense: ambiguous (0.3799); Ultra-rare (popmax 0.0379%, eas); Associated with hyper-IgM syndrome type 2.

What condition is associated with AICDA p.Arg8Trp (c.22C>T)?

AICDA p.Arg8Trp (c.22C>T) is associated with hyper-IgM syndrome type 2 (ClinVar).

How common is AICDA p.Arg8Trp (c.22C>T) in the general population?

AICDA p.Arg8Trp (c.22C>T) is ultra-rare (popmax 0.0379%, eas) (gnomAD).

What do computational predictors say about AICDA p.Arg8Trp (c.22C>T)?

AlphaMissense predicts ambiguous (score 0.3799) — an in-silico prediction, not a clinical call.

AICDA p.Arg8Trp

c.22C>T · rs763540826 · VCV944441

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3799 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0379%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hyper-IgM syndrome type 2

Computational evidence

Protein change
AlphaMissense	0.3799	ambiguous
REVEL	0.286	benign-leaning
SaProt	LLR -8.80	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -3.7, phastCons 0.002
Regional constraint	o/e 0.86	unconstrained · MANE · 8,480 bp · p 0.018 · regional, not allelic
Overall
CADD	19.34	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 0.0379% East Asian · 17/44,890 alleles

Filtering AF 0.0241% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.00527% 85/1,613,664 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0379%	2,641
Remaining individualsnot grpmax-eligible	0.008%	12,494
European (non-Finnish)	0.005%	19,998
Admixed American	0.00334%	29,980
South Asian	0.0022%	45,511

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: AICDA
Protein: p.Arg8Trp
Coding: c.22C>T
MANE Select: NM_020661
dbSNP: rs763540826
Type: single nucleotide variant
Location: chr12:8606999 (GRCh38)
Gene constraint: LOEUF 1.144 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.43 · 5 PDB
Residue 8: the 'interaction with supt6h' region; an α-helix

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

Disease context

hyper-IgM syndrome type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AICDA p.Arg8Gln Uncertain significance ★ ⚠ same residue
AICDA p.Arg8fs Likely pathogenic ★ same residue
AICDA p.Arg112Cys Pathogenic ★★ same condition
AICDA p.Arg190Ter Pathogenic/Likely pathogenic ★★ same condition
AICDA p.Arg24Trp Pathogenic ★★ same condition
AICDA p.Arg92Ter Pathogenic/Likely pathogenic ★★ same condition
AICDA p.Arg99Ter Pathogenic/Likely pathogenic ★★ same condition
AICDA p.Cys147Ter Pathogenic ★★ 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/aicda-p-arg8trp (accessed [today's date]).

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