Is LRRC8A p.Pro3Leu (c.8C>T) pathogenic?

LRRC8A p.Pro3Leu (c.8C>T) is classified Uncertain significance in LRRC8A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-23). AlphaMissense: likely pathogenic (0.9519); Very rare (popmax 0.00017%, nfe).

How common is LRRC8A p.Pro3Leu (c.8C>T) in the general population?

LRRC8A p.Pro3Leu (c.8C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about LRRC8A p.Pro3Leu (c.8C>T)?

AlphaMissense predicts likely pathogenic (score 0.9519) — an in-silico prediction, not a clinical call.

LRRC8A p.Pro3Leu

c.8C>T · VCV4742869

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9519 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9519	likely pathogenic
REVEL	0.318	indeterminate
SaProt	LLR -4.34	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.37	unconstrained · MANE · 191 bp · p 5.9e-09 · regional, not allelic
Overall
CADD	29.5	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 0.00017% European (non-Finnish) · 2/1,174,210 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,606,496 alleles · very rare exomes 2/1,454,142 · genomes 0/152,354 · joint denominator

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.Pro3Leu
Coding: c.8C>T
MANE Select: NM_019594
Type: single nucleotide variant
Location: chr9:128907172 (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.Pro3= 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-pro3leu (accessed [today's date]).

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