Is AICDA p.Val57Met (c.169G>A) pathogenic?

AICDA p.Val57Met (c.169G>A) is classified Pathogenic/Likely pathogenic in AICDA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-30). AlphaMissense: likely pathogenic (0.9184); Very rare (popmax 0.0022%, sas); Associated with hyper-IgM syndrome type 2.

What condition is associated with AICDA p.Val57Met (c.169G>A)?

AICDA p.Val57Met (c.169G>A) is associated with hyper-IgM syndrome type 2 (ClinVar).

How common is AICDA p.Val57Met (c.169G>A) in the general population?

AICDA p.Val57Met (c.169G>A) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about AICDA p.Val57Met (c.169G>A)?

AlphaMissense predicts likely pathogenic (score 0.9184) — an in-silico prediction, not a clinical call.

AICDA p.Val57Met

c.169G>A · rs786205474 · VCV191031

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9184 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hyper-IgM syndrome type 2

Computational evidence

Protein change
AlphaMissense	0.9184	likely pathogenic ✓ concordant with ClinVar
REVEL	0.402	indeterminate
SaProt	LLR -11.26	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 8,480 bp · p 0.018 · regional, not allelic
Overall
CADD	28.9	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 0.0022% South Asian · 2/91,086 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000136%

Overall 0.000137% 2/1,461,890 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.Val57Met
Coding: c.169G>A
MANE Select: NM_020661
dbSNP: rs786205474
Type: single nucleotide variant
Location: chr12:8605473 (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 57: 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.Val57Ala 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
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-val57met (accessed [today's date]).

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