Is LRRC8A p.Ile33Val (c.97A>G) pathogenic?

LRRC8A p.Ile33Val (c.97A>G) is classified Uncertain significance in LRRC8A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-07). AlphaMissense: likely benign (0.0583); Very rare (popmax 0.00446%, eas).

How common is LRRC8A p.Ile33Val (c.97A>G) in the general population?

LRRC8A p.Ile33Val (c.97A>G) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about LRRC8A p.Ile33Val (c.97A>G)?

AlphaMissense predicts likely benign (score 0.0583) — an in-silico prediction, not a clinical call.

LRRC8A p.Ile33Val

c.97A>G · VCV3697143

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0583 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0583	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	LLR -6.24	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 11	GERP 1, phastCons 1
Regional constraint	o/e 0.37	unconstrained · MANE · 191 bp · p 5.9e-09 · regional, not allelic
Overall
CADD	19.48	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 0.00446% East Asian · 2/44,890 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000558% 9/1,614,082 alleles · very rare exomes 8/1,461,766 · genomes 1/152,316 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,445
South Asian	0.0011%	91,088
European (non-Finnish)	0.000508%	196,670

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.Ile33Val
Coding: c.97A>G
MANE Select: NM_019594
Type: single nucleotide variant
Location: chr9:128907261 (GRCh38)
Gene constraint: LOEUF 0.614 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 85.52 · 13 PDB
Residue 33: an α-helix

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

Similar variants

LRRC8A p.Ile33= Likely benign ★ 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-ile33val (accessed [today's date]).

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