Is LRRC8A p.Arg545Cys (c.1633C>T) pathogenic?

LRRC8A p.Arg545Cys (c.1633C>T) is classified Uncertain significance in LRRC8A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-26). AlphaMissense: likely benign (0.2156); Ultra-rare (popmax 0.0164%, mid).

How common is LRRC8A p.Arg545Cys (c.1633C>T) in the general population?

LRRC8A p.Arg545Cys (c.1633C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about LRRC8A p.Arg545Cys (c.1633C>T)?

AlphaMissense predicts likely benign (score 0.2156) — an in-silico prediction, not a clinical call.

LRRC8A p.Arg545Cys

c.1633C>T · VCV3540288

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2156 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2156	likely benign
REVEL	0.176	moderately benign-leaning
SaProt	LLR -9.51	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP -0.32, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 1,645 bp · p 8.8e-32 · regional, not allelic
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.00254% 41/1,613,332 alleles · ultra-rare exomes 34/1,461,134 · genomes 7/152,198 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
African / African-American	0.00667%	14,986
Remaining individualsnot grpmax-eligible	0.0064%	15,620
European (non-Finnish)	0.00237%	42,144
East Asian	0.00223%	44,906
Admixed American	0.00167%	60,002
South Asian	0.0011%	91,084

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.Arg545Cys
Coding: c.1633C>T
MANE Select: NM_019594
Type: single nucleotide variant
Location: chr9:128908797 (GRCh38)
Gene constraint: LOEUF 0.614 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 85.52 · 13 PDB
Residue 545: a UniProt-annotated variant site (found in a patient with sertoli cell-only syndrome; uncertain significance)

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

Similar variants

LRRC8A p.Arg545His 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
LRRC8A p.Arg262Cys Uncertain significance ★★ ⚠ same type
LRRC8A p.Arg496Gln 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-arg545cys (accessed [today's date]).

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