Is LRRC8A p.Pro486= (c.1458C>T) pathogenic?

LRRC8A p.Pro486= (c.1458C>T) is classified Benign/Likely benign in LRRC8A (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-01). Common (popmax 5.77%, afr) — too common for a highly-penetrant pathogenic allele; Associated with agammaglobulinemia 5, autosomal dominant.

What condition is associated with LRRC8A p.Pro486= (c.1458C>T)?

LRRC8A p.Pro486= (c.1458C>T) is associated with agammaglobulinemia 5, autosomal dominant (ClinVar).

LRRC8A p.Pro486=

Q: How common is LRRC8A p.Pro486= (c.1458C>T) in the general population?

LRRC8A p.Pro486= (c.1458C>T) is common (popmax 5.77%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1458C>T · rs11999276 · VCV776451

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 5.77%, afr) — 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 -20	GERP -4
Overall
CADD	0.03	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.77% African / African-American · 4,327/75,034 alleles

Filtering AF 5.62% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.56%

Overall 0.369% 5,944/1,612,566 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.77%	17
Middle Eastern	0.693%	144
Remaining individualsnot grpmax-eligible	0.559%	179
Admixed American	0.555%	180
East Asian	0.486%	206
European (non-Finnish)	0.0548%	1,824
South Asian	0.0286%	3,502
Finnishnot grpmax-eligible	0.00319%	31,367

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.Pro486=
Coding: c.1458C>T
MANE Select: NM_019594
dbSNP: rs11999276
Type: single nucleotide variant
Location: chr9:128908622 (GRCh38)
Gene constraint: LOEUF 0.614 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 85.52 · 13 PDB
Residue 486: 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.Arg492= 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

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-pro486 (accessed [today's date]).

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