Is LRRC8A p.Ser553Arg (c.1659C>G) pathogenic?

LRRC8A p.Ser553Arg (c.1659C>G) is classified Uncertain significance in LRRC8A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-13). AlphaMissense: likely pathogenic (0.9993); Absent from gnomAD v4.1.

How common is LRRC8A p.Ser553Arg (c.1659C>G) in the general population?

LRRC8A p.Ser553Arg (c.1659C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LRRC8A p.Ser553Arg (c.1659C>G)?

AlphaMissense predicts likely pathogenic (score 0.9993) — an in-silico prediction, not a clinical call.

LRRC8A p.Ser553Arg

c.1659C>G · VCV4049376

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9993 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9993	likely pathogenic · top 2% in LRRC8A
REVEL	0.188	benign-leaning
SaProt	LLR -9.49	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 1, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 1,645 bp · p 8.8e-32 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: LRRC8A
Protein: p.Ser553Arg
Coding: c.1659C>G
MANE Select: NM_019594
Type: single nucleotide variant
Location: chr9:128908823 (GRCh38)
Gene constraint: LOEUF 0.614 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 85.52 · 13 PDB
Residue 553: a β-strand

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

Similar variants

LRRC8A p.Ser553Asn 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-ser553arg (accessed [today's date]).

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