Is RELN p.Phe2836= (c.8508C>T) pathogenic?

RELN p.Phe2836= (c.8508C>T) is classified Benign/Likely benign in RELN (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-03). Common (popmax 5.44%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with Norman-Roberts syndrome.

What condition is associated with RELN p.Phe2836= (c.8508C>T)?

RELN p.Phe2836= (c.8508C>T) is associated with Norman-Roberts syndrome, familial temporal lobe epilepsy 7 (ClinVar).

RELN p.Phe2836=

Q: How common is RELN p.Phe2836= (c.8508C>T) in the general population?

RELN p.Phe2836= (c.8508C>T) is common (popmax 5.44%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.8508C>T · rs2229862 · VCV95233

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

gnomAD v4.1

Common

common (popmax 5.44%, nfe) — 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 6.7	GERP 0.79, phastCons 1
Overall
CADD	9.234	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.44% European (non-Finnish) · 64,237/1,179,814 alleles

Filtering AF 5.41% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.39%

Overall 4.67% 75,294/1,613,868 alleles · common exomes 69,699/1,461,624 · genomes 5,595/152,244 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	5.44%	18
Finnishnot grpmax-eligible	5.03%	20
Remaining individualsnot grpmax-eligible	4.21%	24
Ashkenazi Jewishnot grpmax-eligible	3.65%	27
Admixed American	3.38%	30
South Asian	1.45%	69
Middle Eastern	1.35%	74
African / African-American	0.913%	110
Amishnot grpmax-eligible	0.219%	456
East Asian	0.0134%	7,480

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.Phe2836=
Coding: c.8508C>T
MANE Select: NM_005045
dbSNP: rs2229862
Type: single nucleotide variant
Location: chr7:103500904 (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.Phe2836Val Likely benign ★ 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
RELN c.6072+3A>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-phe2836 (accessed [today's date]).

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