Is AICDA p.Pro123Leu (c.368C>T) pathogenic?

AICDA p.Pro123Leu (c.368C>T) is classified Uncertain significance in AICDA (ClinVar, Single submitter, 1 submitter; last evaluated 2019-05-25). AlphaMissense: ambiguous (0.5531); Absent from gnomAD v4.1; Associated with hyper-IgM syndrome type 2.

What condition is associated with AICDA p.Pro123Leu (c.368C>T)?

AICDA p.Pro123Leu (c.368C>T) is associated with hyper-IgM syndrome type 2 (ClinVar).

How common is AICDA p.Pro123Leu (c.368C>T) in the general population?

AICDA p.Pro123Leu (c.368C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AICDA p.Pro123Leu (c.368C>T)?

AlphaMissense predicts ambiguous (score 0.5531) — an in-silico prediction, not a clinical call.

AICDA p.Pro123Leu

c.368C>T · rs1941265632 · VCV851058

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5531 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hyper-IgM syndrome type 2

Computational evidence

Protein change
AlphaMissense	0.5531	ambiguous
REVEL	0.265	benign-leaning
SaProt	LLR -7.38	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 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 8,480 bp · p 0.018 · regional, not allelic
Overall
CADD	24.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AICDA
Protein: p.Pro123Leu
Coding: c.368C>T
MANE Select: NM_020661
dbSNP: rs1941265632
Type: single nucleotide variant
Location: chr12:8605274 (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 123: the cmp/dcmp-type deaminase domain; 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.Pro123= Benign/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
AICDA p.Cys87Arg 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-pro123leu (accessed [today's date]).

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