Is LRRC8A p.Phe69Leu (c.207C>A) pathogenic?

LRRC8A p.Phe69Leu (c.207C>A) is classified Uncertain significance in LRRC8A (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-12). AlphaMissense: ambiguous (0.3404); Absent from gnomAD v4.1.

How common is LRRC8A p.Phe69Leu (c.207C>A) in the general population?

LRRC8A p.Phe69Leu (c.207C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LRRC8A p.Phe69Leu (c.207C>A)?

AlphaMissense predicts ambiguous (score 0.3404) — an in-silico prediction, not a clinical call.

LRRC8A p.Phe69Leu

c.207C>A · rs2131016950 · VCV1518695

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3404 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3404	ambiguous
REVEL	0.182	moderately benign-leaning
SaProt	LLR -5.63	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 0.57	GERP -1.2, phastCons 0.88
Regional constraint	o/e 1.09	unconstrained · MANE · 106 bp · p 0.55 · regional, not allelic
Overall
CADD	15.61	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

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.Phe69Leu
Coding: c.207C>A
MANE Select: NM_019594
dbSNP: rs2131016950
Type: single nucleotide variant
Location: chr9:128907371 (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-phe69leu (accessed [today's date]).

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