Is RELN p.Glu592= (c.1776A>G) pathogenic?

RELN p.Glu592= (c.1776A>G) is classified Benign in RELN (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). Common (popmax 18.8%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Norman-Roberts syndrome.

What condition is associated with RELN p.Glu592= (c.1776A>G)?

RELN p.Glu592= (c.1776A>G) is associated with Norman-Roberts syndrome, familial temporal lobe epilepsy 7 (ClinVar).

RELN p.Glu592=

Q: How common is RELN p.Glu592= (c.1776A>G) in the general population?

RELN p.Glu592= (c.1776A>G) is common (popmax 18.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1776A>G · rs2072403 · VCV130115

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Common

common (popmax 18.8%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

Norman-Roberts syndrome

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 0.1	GERP -0.86, phastCons 0.92
Overall
CADD	7.098	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 18.8% African / African-American · 14,031/74,680 alleles

Filtering AF 18.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 18.4%

Overall 5.93% 95,474/1,610,778 alleles · common exomes 81,210/1,459,118 · genomes 14,264/151,660 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	18.8%	5
East Asian	13.7%	7
Admixed American	10.2%	10
Finnishnot grpmax-eligible	7.42%	13
Amishnot grpmax-eligible	6.92%	14
Remaining individualsnot grpmax-eligible	5.99%	17
European (non-Finnish)	4.7%	21
Ashkenazi Jewishnot grpmax-eligible	4.24%	24
South Asian	4.19%	24
Middle Eastern	3.56%	28

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.Glu592=
Coding: c.1776A>G
MANE Select: NM_005045
dbSNP: rs2072403
Type: single nucleotide variant
Location: chr7:103651777 (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

Norman-Roberts syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial temporal lobe epilepsy 7

Similar variants

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
RELN c.2465+5G>T Uncertain significance ★★ same condition
RELN c.6072+3A>G Uncertain significance ★★ same condition
RELN c.6072+4C>G 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-glu592 (accessed [today's date]).

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