Is LRRC8A p.Glu665= (c.1995G>A) pathogenic?

LRRC8A p.Glu665= (c.1995G>A) is classified Benign in LRRC8A (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-01). Low-frequency (popmax 1.49%, afr); Associated with agammaglobulinemia 5, autosomal dominant.

What condition is associated with LRRC8A p.Glu665= (c.1995G>A)?

LRRC8A p.Glu665= (c.1995G>A) is associated with agammaglobulinemia 5, autosomal dominant (ClinVar).

How common is LRRC8A p.Glu665= (c.1995G>A) in the general population?

LRRC8A p.Glu665= (c.1995G>A) is low-frequency (popmax 1.49%, afr) (gnomAD).

LRRC8A p.Glu665=

c.1995G>A · rs11999752 · VCV776453

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.49%, afr)

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 10	GERP 2, phastCons 1
Overall
CADD	9.461	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.49% African / African-American · 1,116/75,038 alleles

Filtering AF 1.41% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.39%

Overall 0.139% 2,250/1,614,124 alleles · low-frequency exomes 1,478/1,461,840 · genomes 772/152,284 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.49%	67
East Asian	0.423%	236
Middle Eastern	0.33%	303
Admixed American	0.317%	316
Remaining individualsnot grpmax-eligible	0.242%	414
European (non-Finnish)	0.0475%	2,107
South Asian	0.0231%	4,337
Finnishnot grpmax-eligible	0.00313%	31,994

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.Glu665=
Coding: c.1995G>A
MANE Select: NM_019594
dbSNP: rs11999752
Type: single nucleotide variant
Location: chr9:128909159 (GRCh38)
Gene constraint: LOEUF 0.614 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 85.52 · 13 PDB

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.Glu665Gln Uncertain significance ★ ⚠ same residue
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.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-glu665 (accessed [today's date]).

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