Is LRRC8A p.Arg492= (c.1476T>C) pathogenic?

LRRC8A p.Arg492= (c.1476T>C) is classified Benign in LRRC8A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Common (popmax 77.6%, amr) — too common for a highly-penetrant pathogenic allele; Associated with agammaglobulinemia 5, autosomal dominant.

What condition is associated with LRRC8A p.Arg492= (c.1476T>C)?

LRRC8A p.Arg492= (c.1476T>C) is associated with agammaglobulinemia 5, autosomal dominant (ClinVar).

LRRC8A p.Arg492=

Q: How common is LRRC8A p.Arg492= (c.1476T>C) in the general population?

LRRC8A p.Arg492= (c.1476T>C) is common (popmax 77.6%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1476T>C · rs3750319 · VCV403061

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 77.6%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

agammaglobulinemia 5, autosomal dominant

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 -4
Overall
CADD	0.136	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 77.6% Admixed American · 46,534/59,954 alleles

Filtering AF 77% ClinGen BA1/BS1 input FAF95, joint · FAF99 76.8%

Overall 69.8% 1,125,073/1,612,392 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	81.9%	1
Finnishnot grpmax-eligible	80.3%	1
Admixed Americangrpmax	77.6%	1
Ashkenazi Jewishnot grpmax-eligible	74.5%	1
Middle Eastern	72.7%	1
European (non-Finnish)	71.4%	1
East Asian	70.7%	1
Remaining individualsnot grpmax-eligible	68.8%	1
South Asian	67.4%	1
African / African-American	29.9%	3

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: LRRC8A
Protein: p.Arg492=
Coding: c.1476T>C
MANE Select: NM_019594
dbSNP: rs3750319
Type: single nucleotide variant
Location: chr9:128908640 (GRCh38)
Gene constraint: LOEUF 0.614 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 85.52 · 13 PDB
Residue 492: an α-helix

Full LRRC8A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

agammaglobulinemia 5, autosomal dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LRRC8A p.Asp703Asn Uncertain significance ★★ ⚠ same condition
LRRC8A c.2157+11C>T Benign ★★ same condition
LRRC8A p.Ala11= Likely benign ★★ same condition
LRRC8A p.Asp258= Benign ★★ same condition
LRRC8A p.Cys601= Benign ★★ same condition
LRRC8A p.Glu665= Benign ★★ same condition
LRRC8A p.Leu706= Benign ★★ same condition
LRRC8A p.Pro457= Benign/Likely benign ★★ 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/lrrc8a-p-arg492 (accessed [today's date]).

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