Is LRRC8A p.Thr85Ser (c.253A>T) pathogenic?

LRRC8A p.Thr85Ser (c.253A>T) is classified Uncertain significance in LRRC8A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-31). AlphaMissense: likely benign (0.0676); Absent from gnomAD v4.1.

How common is LRRC8A p.Thr85Ser (c.253A>T) in the general population?

LRRC8A p.Thr85Ser (c.253A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LRRC8A p.Thr85Ser (c.253A>T)?

AlphaMissense predicts likely benign (score 0.0676) — an in-silico prediction, not a clinical call.

LRRC8A p.Thr85Ser

c.253A>T · rs2491862607 · VCV2810962

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0676 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0676	likely benign
REVEL	0.118	moderately benign-leaning
SaProt	LLR -6.73	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 9.3	GERP 1.9, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 106 bp · p 0.55 · regional, not allelic
Overall
CADD	12.51	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

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.Thr85Ser
Coding: c.253A>T
MANE Select: NM_019594
dbSNP: rs2491862607
Type: single nucleotide variant
Location: chr9:128907417 (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.Thr85Ile 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-thr85ser (accessed [today's date]).

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