Is IGLL1 p.Arg2Lys (c.5G>A) pathogenic?

IGLL1 p.Arg2Lys (c.5G>A) is classified Uncertain significance in IGLL1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-02). AlphaMissense: likely benign (0.1311); Ultra-rare (popmax 0.0195%, eas); Associated with agammaglobulinemia 2, autosomal recessive.

What condition is associated with IGLL1 p.Arg2Lys (c.5G>A)?

IGLL1 p.Arg2Lys (c.5G>A) is associated with agammaglobulinemia 2, autosomal recessive (ClinVar).

How common is IGLL1 p.Arg2Lys (c.5G>A) in the general population?

IGLL1 p.Arg2Lys (c.5G>A) is ultra-rare (popmax 0.0195%, eas) (gnomAD).

What do computational predictors say about IGLL1 p.Arg2Lys (c.5G>A)?

AlphaMissense predicts likely benign (score 0.1311) — an in-silico prediction, not a clinical call.

IGLL1 p.Arg2Lys

c.5G>A · rs1236663187 · VCV2166215

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1311 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0195%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

agammaglobulinemia 2, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.1311	likely benign
REVEL	0.157	moderately benign-leaning
SaProt	LLR -7.20	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.39	GERP -1.9
Regional constraint	o/e 1.02	unconstrained · MANE · 6,921 bp · p 0.75 · regional, not allelic
Overall
CADD	7.076	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 0.0195% East Asian · 8/41,124 alleles

Filtering AF 0.00963% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00701%

Overall 0.000585% 9/1,539,002 alleles · ultra-rare exomes 6/1,386,790 · genomes 3/152,212 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0195%	5,140
European (non-Finnish)	8.72e-05%	1,147,076

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: IGLL1
Protein: p.Arg2Lys
Coding: c.5G>A
MANE Select: NM_020070
dbSNP: rs1236663187
Type: single nucleotide variant
Location: chr22:23580186 (GRCh38)
Gene constraint: LOEUF 1.844 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 75.19 · 3 PDB

Full IGLL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

agammaglobulinemia 2, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

IGLL1 p.Arg2Thr Uncertain significance ★ ⚠ same residue
IGLL1 p.Ala12Val Uncertain significance ★★ ⚠ same condition
IGLL1 p.Ala174Ser Uncertain significance ★★ ⚠ same condition
IGLL1 p.Arg23His Uncertain significance ★★ ⚠ same condition
IGLL1 p.Arg40Cys Uncertain significance ★★ ⚠ same condition
IGLL1 p.Arg48Gly Uncertain significance ★★ ⚠ same condition
IGLL1 p.Arg60Gln Uncertain significance ★★ ⚠ same condition
IGLL1 p.Arg60Gly Uncertain significance ★★ ⚠ 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/igll1-p-arg2lys (accessed [today's date]).

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