# NM_014813.3(LRIG2):c.993del (p.Phe331fs)

https://sugi.bio/variant/lrig2-p-phe331fs

## Summary

**LRIG2 p.Phe331fs (c.993del)** is classified **Uncertain significance** in LRIG2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2018-09-16). Very rare (popmax 0.00133%, afr).

**At a glance:** Uncertain significance · review: No assertion criteria · rsID rs1326615116 · 1 submitter · very rare (popmax 0.00133%, afr)

## For patients & families {#patients}

This is a change in the LRIG2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [LRIG2](https://sugi.bio/atlas/gene/LRIG2/) |
| Protein change (HGVS p.) | p.Phe331fs |
| Coding change (HGVS c.) | c.993del |
| MANE Select transcript | [NM_014813](https://www.ncbi.nlm.nih.gov/nuccore/NM_014813) |
| dbSNP | [rs1326615116](https://www.ncbi.nlm.nih.gov/snp/rs1326615116/) |
| Variant type | Deletion |
| Location | chr1:113096265-113096265 (GRCh38) |
| ClinVar | [VCV591212](https://www.ncbi.nlm.nih.gov/clinvar/variation/591212/) |

**All HGVS expressions:** `NC_000001.10:g.113638889del`, `NC_000001.11:g.113096267del`, `NG_042819.1:g.28098del`, `NM_001312686.2:c.684del`, `NM_014813.3:c.993del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 0.398, GERP -0.058, phastCons 0.992 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.95, pLI 7.349e-19. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 8 of 18**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 33.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00133%** (afr) · 1/74,920 in the highest group · 1/1,614,012 alleles overall — very rare (popmax 0.00133%, afr).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**LRIG2** population constraint: LOEUF 0.95, pLI 7.349e-19, missense-Z 1.5155. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 74.87, 53% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2018-09-16.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Gharavi Laboratory, Columbia University | Uncertain significance | no assertion criteria provided | research | 2018-09-16 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related LRIG2 variant pages (same residue, condition, or type): [LRIG2 p.Phe331Leu](/variant/lrig2-p-phe331leu), [LRIG2 p.Glu926fs](/variant/lrig2-p-glu926fs), [LRIG2 p.Leu6fs](/variant/lrig2-p-leu6fs), [LRIG2 p.Ser175fs](/variant/lrig2-p-ser175fs), [LRIG2 p.Thr363_Leu364insTer](/variant/lrig2-p-thr363-leu364inster), [LRIG2 p.Arg224fs](/variant/lrig2-p-arg224fs), [LRIG2 p.Glu410fs](/variant/lrig2-p-glu410fs), [LRIG2 p.Ser697fs](/variant/lrig2-p-ser697fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 591212). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*