Is RELN p.Ala2394= (c.7182G>A) pathogenic?

RELN p.Ala2394= (c.7182G>A) is classified Likely benign in RELN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-01). Ultra-rare (popmax 0.0117%, amr); Associated with Norman-Roberts syndrome.

What condition is associated with RELN p.Ala2394= (c.7182G>A)?

RELN p.Ala2394= (c.7182G>A) is associated with Norman-Roberts syndrome, familial temporal lobe epilepsy 7, epilepsy, familial temporal lobe, 1 (ClinVar).

How common is RELN p.Ala2394= (c.7182G>A) in the general population?

RELN p.Ala2394= (c.7182G>A) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

RELN p.Ala2394=

c.7182G>A · rs879182818 · VCV1097359

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

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 0.99	GERP -0.51, phastCons 0.99
Overall
CADD	8.585	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0117% Admixed American · 7/59,984 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00149% 24/1,613,550 alleles · ultra-rare exomes 22/1,461,382 · genomes 2/152,168 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,569
Remaining individualsnot grpmax-eligible	0.0032%	31,234
Finnishnot grpmax-eligible	0.00156%	64,012
European (non-Finnish)	0.0011%	90,743
South Asian	0.0011%	91,058

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.Ala2394=
Coding: c.7182G>A
MANE Select: NM_005045
dbSNP: rs879182818
Type: single nucleotide variant
Location: chr7:103535483 (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 epilepsy, familial temporal lobe, 1

Similar variants

RELN p.Ala2394Thr Uncertain significance ★ ⚠ same residue
RELN p.Ala2394Val 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
RELN c.2465+5G>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-ala2394 (accessed [today's date]).

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