# NM_005045.4(RELN):c.1918C>T (p.Pro640Ser)

https://sugi.bio/variant/reln-p-pro640ser

## Summary

**RELN p.Pro640Ser (c.1918C>T)** is classified **Uncertain significance** in RELN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-01). AlphaMissense: likely pathogenic (0.799); Very rare (popmax 0.000339%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.000339%, nfe)

## For patients & families {#patients}

This is a change in the RELN 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 | [RELN](https://sugi.bio/atlas/gene/RELN/) |
| Protein change (HGVS p.) | p.Pro640Ser |
| Coding change (HGVS c.) | c.1918C>T |
| MANE Select transcript | [NM_005045](https://www.ncbi.nlm.nih.gov/nuccore/NM_005045) |
| Variant type | single nucleotide variant |
| Location | chr7:103650358-103650358 (GRCh38) |
| ClinVar | [VCV3341851](https://www.ncbi.nlm.nih.gov/clinvar/variation/3341851/) |

**All HGVS expressions:** `NC_000007.13:g.103290805G>A`, `NC_000007.14:g.103650358G>A`, `NG_011877.2:g.344159C>T`, `NM_005045.4:c.1918C>T`, `NM_173054.3:c.1918C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.799)
- REVEL 0.517 (indeterminate)
- SpliceAI predicts **acceptor gain** (Δ 0.39) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.897, GERP 1.96, phastCons 1 — highly conserved (agrees)
- **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 32.0**. 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.*
- 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 deltas (raw): acceptor loss **0.12**, donor loss **0.00**, acceptor gain **0.39**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.12**, donor loss **0.00**, acceptor gain **0.39**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.000339%** (nfe) · FAF95 7.9e-05% · FAF99 5.4e-05% · 4/1,178,818 in the highest group · 4/1,612,288 alleles overall — very rare (popmax 0.000339%, nfe).

*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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-08-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-08-01 |

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

## Similar variants {#similar}

Related RELN variant pages (same residue, condition, or type): [RELN p.Pro640Leu](/variant/reln-p-pro640leu), [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 2026-10-15); 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 3341851). 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.*