Is IGLL1 p.Arg74= (c.222C>T) pathogenic?

IGLL1 p.Arg74= (c.222C>T) is classified Likely benign in IGLL1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-25). Ultra-rare (popmax 0.0373%, afr); Associated with agammaglobulinemia 2, autosomal recessive.

What condition is associated with IGLL1 p.Arg74= (c.222C>T)?

IGLL1 p.Arg74= (c.222C>T) is associated with agammaglobulinemia 2, autosomal recessive (ClinVar).

How common is IGLL1 p.Arg74= (c.222C>T) in the general population?

IGLL1 p.Arg74= (c.222C>T) is ultra-rare (popmax 0.0373%, afr) (gnomAD).

IGLL1 p.Arg74=

c.222C>T · rs111509516 · VCV1100005

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0373%, afr)

Conditions

agammaglobulinemia 2, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -11	GERP -2.6
Overall
CADD	3.761	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0373% African / African-American · 28/75,004 alleles

Filtering AF 0.0265% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0229%

Overall 0.00421% 68/1,613,556 alleles · ultra-rare exomes 50/1,461,294 · genomes 18/152,262 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0373%	2,679
Remaining individualsnot grpmax-eligible	0.016%	6,248
South Asian	0.0121%	8,278
East Asian	0.00669%	14,957
Finnishnot grpmax-eligible	0.00312%	32,018
Admixed American	0.00167%	60,024
European (non-Finnish)	0.0011%	90,732

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.Arg74=
Coding: c.222C>T
MANE Select: NM_020070
dbSNP: rs111509516
Type: single nucleotide variant
Location: chr22:23575067 (GRCh38)
Gene constraint: LOEUF 1.844 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 75.19 · 3 PDB
Residue 74: an α-helix

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.Arg74Cys Uncertain significance ★ ⚠ same residue
IGLL1 p.Arg74His 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.Arg2Lys Uncertain significance ★★ ⚠ same condition
IGLL1 p.Arg40Cys Uncertain significance ★★ ⚠ same condition
IGLL1 p.Arg48Gly 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-arg74 (accessed [today's date]).

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