Is AICDA p.Cys87Arg (c.259T>C) pathogenic?

AICDA p.Cys87Arg (c.259T>C) is classified Pathogenic/Likely pathogenic in AICDA (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-03-17). AlphaMissense: likely pathogenic (0.9887); Very rare (popmax 0.00127%, nfe); Associated with hyper-IgM syndrome type 2.

What condition is associated with AICDA p.Cys87Arg (c.259T>C)?

AICDA p.Cys87Arg (c.259T>C) is associated with hyper-IgM syndrome type 2 (ClinVar).

How common is AICDA p.Cys87Arg (c.259T>C) in the general population?

AICDA p.Cys87Arg (c.259T>C) is very rare (popmax 0.00127%, nfe) (gnomAD).

What do computational predictors say about AICDA p.Cys87Arg (c.259T>C)?

AlphaMissense predicts likely pathogenic (score 0.9887) — an in-silico prediction, not a clinical call.

AICDA p.Cys87Arg

c.259T>C · rs762590894 · VCV617969

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9887 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00127%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyper-IgM syndrome type 2

Computational evidence

Protein change
AlphaMissense	0.9887	likely pathogenic ✓ concordant with ClinVar · top 5% in AICDA
REVEL	0.978	strongly pathogenic-leaning
SaProt	LLR -6.01	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 8,480 bp · p 0.018 · regional, not allelic
Overall
CADD	29.6	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 0.00127% European (non-Finnish) · 15/1,180,042 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.000991% 16/1,614,110 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,040
European (non-Finnish)grpmax	0.00127%	78,670

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Cys87Arg
Coding: c.259T>C
MANE Select: NM_020661
dbSNP: rs762590894
Type: single nucleotide variant
Location: chr12:8605383 (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 87: the cmp/dcmp-type deaminase domain; a UniProt-annotated variant site (in higm2; uncertain significance); an α-helix; a binding site

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.Cys87Ser Pathogenic/Likely pathogenic ★★ same residue
AICDA p.Cys87Gly Conflicting classifications of pathogenicity ★ ⚠ 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-cys87arg (accessed [today's date]).

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