Is RELN p.Ile2313= (c.6939T>C) pathogenic?

RELN p.Ile2313= (c.6939T>C) is classified Conflicting classifications of pathogenicity in RELN (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-04-01). Rare (popmax 0.22%, afr); Associated with Norman-Roberts syndrome.

What condition is associated with RELN p.Ile2313= (c.6939T>C)?

RELN p.Ile2313= (c.6939T>C) is associated with Norman-Roberts syndrome, familial temporal lobe epilepsy 7 (ClinVar).

How common is RELN p.Ile2313= (c.6939T>C) in the general population?

RELN p.Ile2313= (c.6939T>C) is rare (popmax 0.22%, afr) (gnomAD).

RELN p.Ile2313=

c.6939T>C · rs113498433 · VCV212044

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

rare (popmax 0.22%, afr)

Conditions

Norman-Roberts syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.049	GERP -3.4, phastCons 0.008
Overall
CADD	2.261	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.22% African / African-American · 165/75,068 alleles

Filtering AF 0.192% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.182%

Overall 0.0127% 205/1,614,004 alleles · rare exomes 118/1,461,646 · genomes 87/152,358 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.22%	455
Middle Eastern	0.0825%	1,212
Remaining individualsnot grpmax-eligible	0.0368%	2,717
Admixed American	0.0167%	6,003
South Asian	0.0011%	91,088
European (non-Finnish)	8.48e-05%	1,179,828

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.Ile2313=
Coding: c.6939T>C
MANE Select: NM_005045
dbSNP: rs113498433
Type: single nucleotide variant
Location: chr7:103539319 (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.Ile2313Thr 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-ile2313 (accessed [today's date]).

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