Is LRRC8A p.Arg685= (c.2055C>G) pathogenic?

LRRC8A p.Arg685= (c.2055C>G) is classified Likely benign in LRRC8A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-25). Ultra-rare (popmax 0.0133%, afr).

How common is LRRC8A p.Arg685= (c.2055C>G) in the general population?

LRRC8A p.Arg685= (c.2055C>G) is ultra-rare (popmax 0.0133%, afr) (gnomAD).

LRRC8A p.Arg685=

c.2055C>G · rs942553528 · VCV2968761

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, afr)

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 1.4	GERP -0.25, phastCons 1
Overall
CADD	7.759	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% African / African-American · 10/74,950 alleles

Filtering AF 0.00723% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0055%

Overall 0.000682% 11/1,614,072 alleles · ultra-rare exomes 4/1,461,812 · genomes 7/152,260 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0133%	7,495
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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.Arg685=
Coding: c.2055C>G
MANE Select: NM_019594
dbSNP: rs942553528
Type: single nucleotide variant
Location: chr9:128909219 (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

Similar variants

LRRC8A p.Arg685Cys Uncertain significance ★ ⚠ same residue
LRRC8A p.Arg685His Uncertain significance ★ ⚠ same residue
LRRC8A p.Arg685Leu Uncertain significance ★ same residue
LRRC8A p.Ala497Val Uncertain significance ★★ ⚠ same type
LRRC8A p.Arg148His Uncertain significance ★★ ⚠ same type
LRRC8A p.Arg214Gln Uncertain significance ★★ ⚠ same type
LRRC8A p.Arg218Gln Uncertain significance ★★ ⚠ same type
LRRC8A p.Arg218Trp Uncertain significance ★★ ⚠ same type

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-arg685 (accessed [today's date]).

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