Is AICDA p.Ile136Met (c.408A>G) pathogenic?

AICDA p.Ile136Met (c.408A>G) is classified Uncertain significance in AICDA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-11). AlphaMissense: likely benign (0.1229); Very rare (popmax 0.00339%, nfe); Associated with hyper-IgM syndrome type 2.

What condition is associated with AICDA p.Ile136Met (c.408A>G)?

AICDA p.Ile136Met (c.408A>G) is associated with hyper-IgM syndrome type 2 (ClinVar).

How common is AICDA p.Ile136Met (c.408A>G) in the general population?

AICDA p.Ile136Met (c.408A>G) is very rare (popmax 0.00339%, nfe) (gnomAD).

What do computational predictors say about AICDA p.Ile136Met (c.408A>G)?

AlphaMissense predicts likely benign (score 0.1229) — an in-silico prediction, not a clinical call.

AICDA p.Ile136Met

c.408A>G · rs887002786 · VCV1493976

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1229 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00339%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hyper-IgM syndrome type 2

Computational evidence

Protein change
AlphaMissense	0.1229	likely benign
REVEL	0.295	indeterminate
SaProt	LLR -7.49	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -3.4
Regional constraint	o/e 0.86	unconstrained · MANE · 8,480 bp · p 0.018 · regional, not allelic
Overall
CADD	10.67	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00339% European (non-Finnish) · 40/1,180,032 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00225%

Overall 0.00273% 44/1,613,996 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00339%	29,501
Admixed American	0.00167%	59,994
Remaining individualsnot grpmax-eligible	0.0016%	62,476
African / African-American	0.00133%	74,942
South Asian	0.0011%	91,082

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.Ile136Met
Coding: c.408A>G
MANE Select: NM_020661
dbSNP: rs887002786
Type: single nucleotide variant
Location: chr12:8605234 (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 136: a β-strand

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.Ile136Thr Uncertain significance ★ ⚠ same residue
AICDA p.Ile136Val Uncertain significance ★ ⚠ 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-ile136met (accessed [today's date]).

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