Is AICDA p.Ter199Arg (c.595T>A) pathogenic?

AICDA p.Ter199Arg (c.595T>A) is classified Uncertain significance in AICDA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-27). Very rare (popmax 0.000424%, nfe); Associated with hyper-IgM syndrome type 2.

What condition is associated with AICDA p.Ter199Arg (c.595T>A)?

AICDA p.Ter199Arg (c.595T>A) is associated with hyper-IgM syndrome type 2 (ClinVar).

How common is AICDA p.Ter199Arg (c.595T>A) in the general population?

AICDA p.Ter199Arg (c.595T>A) is very rare (popmax 0.000424%, nfe) (gnomAD).

AICDA p.Ter199Arg

c.595T>A · rs1941232171 · VCV2096713

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

stop-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Conditions

hyper-IgM syndrome type 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	stop-loss	predicted loss-of-function
REVEL	0.326	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Overall
CADD	20.2	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,618 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000342% 5/1,461,416 alleles · very rare

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.Ter199Arg
Coding: c.595T>A
MANE Select: NM_020661
dbSNP: rs1941232171
Type: single nucleotide variant
Location: chr12:8604286 (GRCh38)
Gene constraint: LOEUF 1.144 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.43 · 5 PDB

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.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
AICDA p.Cys87Arg Pathogenic/Likely pathogenic ★★ ⚠ same condition
AICDA p.Cys87Ser Pathogenic/Likely 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-ter199arg (accessed [today's date]).

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