Is LRRC8A p.Val536Ile (c.1606G>A) pathogenic?

LRRC8A p.Val536Ile (c.1606G>A) is classified Benign/Likely benign in LRRC8A (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.1218); Ultra-rare (popmax 0.045%, sas); Associated with agammaglobulinemia 5, autosomal dominant.

What condition is associated with LRRC8A p.Val536Ile (c.1606G>A)?

LRRC8A p.Val536Ile (c.1606G>A) is associated with agammaglobulinemia 5, autosomal dominant (ClinVar).

How common is LRRC8A p.Val536Ile (c.1606G>A) in the general population?

LRRC8A p.Val536Ile (c.1606G>A) is ultra-rare (popmax 0.045%, sas) (gnomAD).

What do computational predictors say about LRRC8A p.Val536Ile (c.1606G>A)?

AlphaMissense predicts likely benign (score 0.1218) — an in-silico prediction, not a clinical call.

LRRC8A p.Val536Ile

c.1606G>A · rs138622041 · VCV722489

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1218 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.045%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

agammaglobulinemia 5, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.1218	likely benign
REVEL	0.121	moderately benign-leaning
SaProt	LLR -5.94	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 12	GERP 0.93, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 1,645 bp · p 8.8e-32 · regional, not allelic
Overall
CADD	22.5	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 0.045% South Asian · 41/91,084 alleles

Filtering AF 0.034% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0302%

Overall 0.086% 1,387/1,613,350 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	3.29%	30
Remaining individualsnot grpmax-eligible	0.278%	359
South Asiangrpmax	0.045%	2,222
European (non-Finnish)	0.0159%	6,277
Admixed American	0.01%	10,004
African / African-American	0.004%	25,021
East Asian	0.00223%	44,892

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val536Ile
Coding: c.1606G>A
MANE Select: NM_019594
dbSNP: rs138622041
Type: single nucleotide variant
Location: chr9:128908770 (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

Disease context

agammaglobulinemia 5, autosomal dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LRRC8A p.Asp703Asn Uncertain significance ★★ ⚠ same condition
LRRC8A c.2157+11C>T Benign ★★ same condition
LRRC8A p.Ala11= Likely benign ★★ same condition
LRRC8A p.Arg492= Benign ★★ same condition
LRRC8A p.Asp258= Benign ★★ same condition
LRRC8A p.Cys601= Benign ★★ same condition
LRRC8A p.Glu665= Benign ★★ same condition
LRRC8A p.Leu706= Benign ★★ same condition

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-val536ile (accessed [today's date]).

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