Is RELN p.Pro1580= (c.4740G>A) pathogenic?

RELN p.Pro1580= (c.4740G>A) is classified Likely benign in RELN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-19). Ultra-rare (popmax 0.0165%, mid); Associated with familial temporal lobe epilepsy 7.

What condition is associated with RELN p.Pro1580= (c.4740G>A)?

RELN p.Pro1580= (c.4740G>A) is associated with familial temporal lobe epilepsy 7, Norman-Roberts syndrome (ClinVar).

How common is RELN p.Pro1580= (c.4740G>A) in the general population?

RELN p.Pro1580= (c.4740G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

RELN p.Pro1580=

c.4740G>A · rs377118940 · VCV1135370

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

familial temporal lobe epilepsy 7

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.3	GERP -4.1
Overall
CADD	1.964	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,056 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00173% 28/1,613,996 alleles · ultra-rare exomes 25/1,461,806 · genomes 3/152,190 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,056
South Asian	0.00439%	22,772
African / African-American	0.00267%	37,462
East Asian	0.00223%	44,896
European (non-Finnish)	0.00161%	62,106
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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: RELN
Protein: p.Pro1580=
Coding: c.4740G>A
MANE Select: NM_005045
dbSNP: rs377118940
Type: single nucleotide variant
Location: chr7:103566608 (GRCh38)
Gene constraint: LOEUF 0.276 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)

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

Disease context

familial temporal lobe epilepsy 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Norman-Roberts syndrome

Similar variants

RELN p.Pro1580Arg Uncertain significance ★ same residue
RELN p.Pro1580Leu Uncertain significance ★ same residue
RELN p.Pro1580Thr Uncertain significance ★ same residue
RELN c.3912+2T>G Likely pathogenic ★★ same condition
RELN c.7349+2T>C Likely pathogenic ★★ same condition
RELN p.Arg1622Ter Pathogenic/Likely pathogenic ★★ same condition
RELN c.1893-3C>T Uncertain significance ★★ same condition
RELN c.227-3C>T Uncertain significance ★★ same condition

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/reln-p-pro1580 (accessed [today's date]).

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