Is RELN p.Ser2257= (c.6771G>A) pathogenic?

RELN p.Ser2257= (c.6771G>A) is classified Likely benign in RELN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-03). Ultra-rare (popmax 0.029%, eas); Associated with Norman-Roberts syndrome.

What condition is associated with RELN p.Ser2257= (c.6771G>A)?

RELN p.Ser2257= (c.6771G>A) is associated with Norman-Roberts syndrome, familial temporal lobe epilepsy 7 (ClinVar).

How common is RELN p.Ser2257= (c.6771G>A) in the general population?

RELN p.Ser2257= (c.6771G>A) is ultra-rare (popmax 0.029%, eas) (gnomAD).

RELN p.Ser2257=

c.6771G>A · rs367867782 · VCV743438

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.029%, eas)

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 -15	GERP -3.3
Overall
CADD	0.323	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.029% East Asian · 13/44,880 alleles

Filtering AF 0.0171% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00341% 55/1,614,106 alleles · ultra-rare exomes 51/1,461,880 · genomes 4/152,226 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.029%	3,452
South Asian	0.0132%	7,590
Remaining individualsnot grpmax-eligible	0.0048%	20,835
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Admixed American	0.00333%	30,004
European (non-Finnish)	0.00203%	49,167

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.Ser2257=
Coding: c.6771G>A
MANE Select: NM_005045
dbSNP: rs367867782
Type: single nucleotide variant
Location: chr7:103540356 (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 p.Ser2257Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
RELN p.Ser2257Pro 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-ser2257 (accessed [today's date]).

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