Is LRIG2 p.Leu409Pro (c.1226T>C) pathogenic?

LRIG2 p.Leu409Pro (c.1226T>C) is classified Uncertain significance in LRIG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-13). AlphaMissense: likely pathogenic (0.9847); Very rare (popmax 0.00113%, sas).

How common is LRIG2 p.Leu409Pro (c.1226T>C) in the general population?

LRIG2 p.Leu409Pro (c.1226T>C) is very rare (popmax 0.00113%, sas) (gnomAD).

What do computational predictors say about LRIG2 p.Leu409Pro (c.1226T>C)?

AlphaMissense predicts likely pathogenic (score 0.9847) — an in-silico prediction, not a clinical call.

LRIG2 p.Leu409Pro

c.1226T>C · rs2525604360 · VCV3120038

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9847 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00113%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9847	likely pathogenic · top 5% in LRIG2
REVEL	0.789	moderately pathogenic-leaning
SaProt	LLR -12.46	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.8, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 34 kb · p 0.4 · regional, not allelic
Overall
CADD	28.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Grpmax group 0.00113% South Asian · 1/88,380 alleles

Overall 6.29e-05% 1/1,590,190 alleles · very rare exomes 1/1,437,816 · genomes 0/152,374 · 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: LRIG2
Protein: p.Leu409Pro
Coding: c.1226T>C
MANE Select: NM_014813
dbSNP: rs2525604360
Type: single nucleotide variant
Location: chr1:113100264 (GRCh38)
Gene constraint: LOEUF 0.95 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.87

Full LRIG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

LRIG2 p.Arg86Trp Uncertain significance ★★ ⚠ same type
LRIG2 p.Glu11Ter Uncertain significance ★★ same type
LRIG2 p.Lys245Arg Uncertain significance ★★ ⚠ same type
LRIG2 c.2531-22G>A Benign ★★ same type
LRIG2 p.Ala2= Likely benign ★★ same type
LRIG2 p.Asp755Glu Benign ★★ same type
LRIG2 p.Ile155Leu Likely benign ★★ same type
LRIG2 p.Pro882Leu Likely benign ★★ 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/lrig2-p-leu409pro (accessed [today's date]).

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