# NM_005045.4(RELN):c.77C>T (p.Ala26Val)

https://sugi.bio/variant/reln-p-ala26val

## Summary

**RELN p.Ala26Val (c.77C>T)** is classified **Conflicting classifications of pathogenicity** in RELN (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-12-01). AlphaMissense: likely benign (0.1521); Rare (popmax 0.54%, afr); Associated with familial temporal lobe epilepsy 7.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs144557847 · 8 submitters · 2 linked conditions · AlphaMissense likely benign · rare (popmax 0.54%, afr)

## For patients & families {#patients}

This is a change in the RELN gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 8 submitters, and is linked to familial temporal lobe epilepsy 7.

*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.*

|  |  |
| --- | --- |
| Diagnostic panels | RELN is a diagnostic-grade gene on 13 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016112/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.Ala26Val |
| Coding change (HGVS c.) | c.77C>T |
| MANE Select transcript | [NM_005045](https://www.ncbi.nlm.nih.gov/nuccore/NM_005045) |
| dbSNP | [rs144557847](https://www.ncbi.nlm.nih.gov/snp/rs144557847/) |
| Variant type | single nucleotide variant |
| Location | chr7:103989280-103989280 (GRCh38) |
| ClinVar | [VCV193299](https://www.ncbi.nlm.nih.gov/clinvar/variation/193299/) |

**All HGVS expressions:** `NC_000007.13:g.103629727G>A`, `NC_000007.14:g.103989280G>A`, `NG_011877.2:g.5237C>T`, `NM_005045.4:c.77C>T`, `NM_173054.3:c.77C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1521)
- REVEL 0.066 (moderately benign-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this tolerated; SaProt makes no call
- Conservation: phyloP 8.313, GERP 1.57, phastCons 1 — highly conserved (differs from AlphaMissense)
- **SaProt:** not scored — SaProt is structure-aware and AlphaFold DB has no model for this protein. That is a property of the dataset, not of the variant, and is not evidence either way.
- CADD: **PHRED 25.4**. 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.*
- Regional missense constraint: **o/e 0.93** across the covering region of the MANE Select transcript (103,557,010–103,989,356), spanning 432,346 bp. Chi-square p 0.0016. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.54%** (afr) · FAF95 0.496% · FAF99 0.479% · 405/75,028 in the highest group · 466/1,613,098 alleles overall — rare (popmax 0.54%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.54% | 185 |
| Remaining individuals (not grpmax-eligible) | 0.056% | 1,785 |
| Middle Eastern | 0.0333% | 3,004 |
| Admixed American | 0.0283% | 3,530 |
| European (non-Finnish) | 0.000593% | 168,532 |

*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}

Residue **26** lies in the reelin domain.

**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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-12-01.

**Submitter consensus:** conflicting (6 Likely benign, 1 Uncertain significance, 1 Benign).

**Submission history:** 8 submissions (2015–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Uncertain significance | criteria provided, single submitter | clinical testing | 2015-12-31 |
| Athena Diagnostics | Benign | criteria provided, single submitter | clinical testing | 2018-11-23 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2022-04-18 |
| Eurofins Ntd Llc (ga) | Likely benign | criteria provided, single submitter | clinical testing | 2017-02-22 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-07-06 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2020-09-10 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2024-04-01 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related RELN variant pages (same residue, condition, or type): [RELN p.Ala26=](/variant/reln-p-ala26), [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 193299). 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.*