Is LRRC8A p.Asp258= (c.774C>T) pathogenic?

LRRC8A p.Asp258= (c.774C>T) is classified Benign in LRRC8A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-02). Common (popmax 6.56%, sas) — too common for a highly-penetrant pathogenic allele; Associated with agammaglobulinemia 5, autosomal dominant.

What condition is associated with LRRC8A p.Asp258= (c.774C>T)?

LRRC8A p.Asp258= (c.774C>T) is associated with agammaglobulinemia 5, autosomal dominant (ClinVar).

LRRC8A p.Asp258=

Q: How common is LRRC8A p.Asp258= (c.774C>T) in the general population?

LRRC8A p.Asp258= (c.774C>T) is common (popmax 6.56%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.774C>T · rs41275930 · VCV439874

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 6.56%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

agammaglobulinemia 5, autosomal dominant

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -0.085, phastCons 1
Overall
CADD	8.142	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.56% South Asian · 5,978/91,072 alleles

Filtering AF 6.43% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.37%

Overall 1.44% 23,198/1,614,076 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	6.56%	15
Middle Eastern	2.19%	46
Ashkenazi Jewishnot grpmax-eligible	1.69%	59
Remaining individualsnot grpmax-eligible	1.32%	76
European (non-Finnish)	1.28%	78
Admixed American	0.718%	139
African / African-American	0.195%	514
Finnishnot grpmax-eligible	0.189%	529
East Asian	0.0111%	8,976

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.Asp258=
Coding: c.774C>T
MANE Select: NM_019594
dbSNP: rs41275930
Type: single nucleotide variant
Location: chr9:128907938 (GRCh38)
Gene constraint: LOEUF 0.614 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 85.52 · 13 PDB
Residue 258: a disulfide bond

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.Asp258Tyr Uncertain significance ★ ⚠ same residue
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.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-asp258 (accessed [today's date]).

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