Is RELN p.Ile3374= (c.10122C>T) pathogenic?

RELN p.Ile3374= (c.10122C>T) is classified Likely benign in RELN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-30). Ultra-rare (popmax 0.0164%, mid); Associated with Norman-Roberts syndrome.

What condition is associated with RELN p.Ile3374= (c.10122C>T)?

RELN p.Ile3374= (c.10122C>T) is associated with Norman-Roberts syndrome, familial temporal lobe epilepsy 7 (ClinVar).

How common is RELN p.Ile3374= (c.10122C>T) in the general population?

RELN p.Ile3374= (c.10122C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

RELN p.Ile3374=

c.10122C>T · rs767729538 · VCV381313

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

Norman-Roberts syndrome

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -0.61	GERP -2, phastCons 0.001
Overall
CADD	9.12	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 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.000805% 13/1,614,024 alleles · ultra-rare exomes 8/1,461,852 · genomes 5/152,172 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
African / African-American	0.00667%	14,985
East Asian	0.00446%	22,441
Admixed American	0.00167%	59,990
South Asian	0.0011%	91,088
European (non-Finnish)	0.000254%	393,342

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.Ile3374=
Coding: c.10122C>T
MANE Select: NM_005045
dbSNP: rs767729538
Type: single nucleotide variant
Location: chr7:103483712 (GRCh38)

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

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-ile3374 (accessed [today's date]).

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