# NM_005045.4(RELN):c.2976G>A (p.Arg992=)

https://sugi.bio/variant/reln-p-arg992

## Summary

**RELN p.Arg992= (c.2976G>A)** is classified **Likely benign** in RELN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-01-19). Very rare (popmax 0.000341%, nfe); Associated with Norman-Roberts syndrome.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs1250895278 · 2 submitters · 2 linked conditions · very rare (popmax 0.000341%, nfe)

## For patients & families {#patients}

This is a change in the RELN gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to Norman-Roberts syndrome.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016780/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [RELN](https://sugi.bio/atlas/gene/RELN/) |
| Protein change (HGVS p.) | p.Arg992= |
| Coding change (HGVS c.) | c.2976G>A |
| MANE Select transcript | [NM_005045](https://www.ncbi.nlm.nih.gov/nuccore/NM_005045) |
| dbSNP | [rs1250895278](https://www.ncbi.nlm.nih.gov/snp/rs1250895278/) |
| Variant type | single nucleotide variant |
| Location | chr7:103610727-103610727 (GRCh38) |
| ClinVar | [VCV493461](https://www.ncbi.nlm.nih.gov/clinvar/variation/493461/) |

**All HGVS expressions:** `NC_000007.13:g.103251174C>T`, `NC_000007.14:g.103610727C>T`, `NG_011877.2:g.383790G>A`, `NM_005045.4:c.2976G>A`, `NM_173054.3:c.2976G>A`

## 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 0.915, GERP -1.79, phastCons 1 — weakly conserved position
- CADD: **PHRED 5.712**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.27 donor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000341%** (nfe) · FAF95 8e-05% · FAF99 5.4e-05% · 4/1,173,000 in the highest group · 5/1,606,050 alleles overall — very rare (popmax 0.000341%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00161% | 62,220 |
| European (non-Finnish) (grpmax) | 0.000341% | 293,250 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**RELN** population constraint: LOEUF 0.276, pLI 1, missense-Z 4.2857; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **lissencephaly with cerebellar hypoplasia** — Definitive (AR)
- **complex neurodevelopmental disorder** — Disputed (AD)

## Protein context {#protein}


**1 experimental structure(s)** (PDB): [8G21](https://www.rcsb.org/structure/8G21).

## What this gene does {#gene-function}

*Describes the biological roles of RELN (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*


### Pathways affected {#pathways}

RELN participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Reelin signalling pathway](https://reactome.org/content/detail/R-HSA-8866376) | other |

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2021-01-19.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2017–2021); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2021-01-19 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2017-10-01 |

## Associated conditions {#conditions}

[Norman-Roberts syndrome](https://sugi.bio/atlas/disease/norman-roberts-syndrome/), [familial temporal lobe epilepsy 7](https://sugi.bio/atlas/disease/familial-temporal-lobe-epilepsy-7/).

**Reported phenotype names (ClinVar):** Norman-Roberts syndrome, not provided, Familial temporal lobe epilepsy 7, Lissencephaly 2 (Norman-Roberts type), none provided.

## Similar variants {#similar}

Related RELN variant pages (same residue, condition, or type): [RELN p.Arg992Lys](/variant/reln-p-arg992lys), [RELN c.3912+2T>G](/variant/reln-c-3912-plus-2t-g), [RELN c.7349+2T>C](/variant/reln-c-7349-plus-2t-c), [RELN p.Arg1622Ter](/variant/reln-p-arg1622ter), [RELN c.1893-3C>T](/variant/reln-c-1893-minus-3c-t), [RELN c.227-3C>T](/variant/reln-c-227-minus-3c-t), [RELN c.2465+5G>T](/variant/reln-c-2465-plus-5g-t), [RELN c.6072+3A>G](/variant/reln-c-6072-plus-3a-g).

### 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 493461). 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.*