Is AICDA p.Arg25His (c.74G>A) pathogenic?

AICDA p.Arg25His (c.74G>A) is classified Benign/Likely benign in AICDA (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-30). AlphaMissense: likely benign (0.0645); Rare (popmax 0.996%, afr); Associated with hyper-IgM syndrome type 2.

What condition is associated with AICDA p.Arg25His (c.74G>A)?

AICDA p.Arg25His (c.74G>A) is associated with hyper-IgM syndrome type 2 (ClinVar).

How common is AICDA p.Arg25His (c.74G>A) in the general population?

AICDA p.Arg25His (c.74G>A) is rare (popmax 0.996%, afr) (gnomAD).

What do computational predictors say about AICDA p.Arg25His (c.74G>A)?

AlphaMissense predicts likely benign (score 0.0645) — an in-silico prediction, not a clinical call.

AICDA p.Arg25His

c.74G>A · rs61730095 · VCV532543

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0645 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.996%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyper-IgM syndrome type 2

Computational evidence

Protein change
AlphaMissense	0.0645	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -5.46	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 4.2	GERP 0.73, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 8,480 bp · p 0.018 · regional, not allelic
Overall
CADD	17.87	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 0.996% African / African-American · 747/75,020 alleles

Filtering AF 0.937% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.913%

Overall 0.0532% 858/1,614,178 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.996%	100
Remaining individualsnot grpmax-eligible	0.0608%	1,645
Admixed American	0.04%	2,501
Middle Eastern	0.0165%	6,062
South Asian	0.00439%	22,770
European (non-Finnish)	0.00373%	26,819

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.Arg25His
Coding: c.74G>A
MANE Select: NM_020661
dbSNP: rs61730095
Type: single nucleotide variant
Location: chr12:8606947 (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 25: the cmp/dcmp-type deaminase domain; a UniProt-annotated variant site (in); the 'interaction with supt6h' region

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.Arg25Cys Uncertain significance ★★ ⚠ same residue
AICDA p.Arg25= Likely benign ★ 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-arg25his (accessed [today's date]).

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