Is RELN p.Ser2676= (c.8028C>T) pathogenic?

RELN p.Ser2676= (c.8028C>T) is classified Likely benign in RELN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-02). Ultra-rare (popmax 0.0164%, mid); Associated with Norman-Roberts syndrome.

What condition is associated with RELN p.Ser2676= (c.8028C>T)?

RELN p.Ser2676= (c.8028C>T) is associated with Norman-Roberts syndrome, familial temporal lobe epilepsy 7 (ClinVar).

How common is RELN p.Ser2676= (c.8028C>T) in the general population?

RELN p.Ser2676= (c.8028C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

RELN p.Ser2676=

c.8028C>T · rs777057396 · VCV542593

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

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 -7.5	GERP -3.9
Overall
CADD	1.232	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00155% 25/1,614,028 alleles · ultra-rare exomes 24/1,461,854 · genomes 1/152,174 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
East Asian	0.00891%	11,221
South Asian	0.00439%	22,767
African / African-American	0.004%	24,977
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	0.00102%	98,335

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.Ser2676=
Coding: c.8028C>T
MANE Select: NM_005045
dbSNP: rs777057396
Type: single nucleotide variant
Location: chr7:103515276 (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.Ser2676Asn Uncertain significance ★ ⚠ same residue
RELN p.Ser2676Thr 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-ser2676 (accessed [today's date]).

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