Is LRRC8A p.Val293Met (c.877G>A) pathogenic?

LRRC8A p.Val293Met (c.877G>A) is classified Uncertain significance in LRRC8A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-11). AlphaMissense: ambiguous (0.5113); Ultra-rare (popmax 0.0165%, mid).

How common is LRRC8A p.Val293Met (c.877G>A) in the general population?

LRRC8A p.Val293Met (c.877G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about LRRC8A p.Val293Met (c.877G>A)?

AlphaMissense predicts ambiguous (score 0.5113) — an in-silico prediction, not a clinical call.

LRRC8A p.Val293Met

c.877G>A · rs754146653 · VCV1365881

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5113 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5113	ambiguous
REVEL	0.258	benign-leaning
SaProt	LLR -5.11	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.92, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 1,645 bp · p 8.8e-32 · regional, not allelic
Overall
CADD	33.0	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

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000682% 11/1,614,062 alleles · ultra-rare exomes 11/1,461,834 · genomes 0/152,228 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Admixed American	0.00667%	15,003
East Asian	0.00223%	44,866
Remaining individualsnot grpmax-eligible	0.0016%	62,512
European (non-Finnish)	0.000339%	295,006

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.Val293Met
Coding: c.877G>A
MANE Select: NM_019594
dbSNP: rs754146653
Type: single nucleotide variant
Location: chr9:128908041 (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.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
LRRC8A p.Arg545Cys 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-val293met (accessed [today's date]).

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