Is AICDA p.Arg127Trp (c.379C>T) pathogenic?

AICDA p.Arg127Trp (c.379C>T) is classified Uncertain significance in AICDA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-20). AlphaMissense: likely pathogenic (0.7446); Very rare (popmax 0.00223%, eas); Associated with hyper-IgM syndrome type 2.

What condition is associated with AICDA p.Arg127Trp (c.379C>T)?

AICDA p.Arg127Trp (c.379C>T) is associated with hyper-IgM syndrome type 2 (ClinVar).

How common is AICDA p.Arg127Trp (c.379C>T) in the general population?

AICDA p.Arg127Trp (c.379C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about AICDA p.Arg127Trp (c.379C>T)?

AlphaMissense predicts likely pathogenic (score 0.7446) — an in-silico prediction, not a clinical call.

AICDA p.Arg127Trp

c.379C>T · rs141451637 · VCV2857650

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7446 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hyper-IgM syndrome type 2

Computational evidence

Protein change
AlphaMissense	0.7446	likely pathogenic
REVEL	0.611	indeterminate
SaProt	LLR -9.93	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP -3, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 8,480 bp · p 0.018 · regional, not allelic
Overall
CADD	24.2	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 0.00223% East Asian · 1/44,896 alleles

Overall 0.000124% 2/1,614,062 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,896
African / African-American	0.00133%	74,956

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.Arg127Trp
Coding: c.379C>T
MANE Select: NM_020661
dbSNP: rs141451637
Type: single nucleotide variant
Location: chr12:8605263 (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 127: 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.Arg127= 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-arg127trp (accessed [today's date]).

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