Is RELN p.Ile1978= (c.5934C>T) pathogenic?

RELN p.Ile1978= (c.5934C>T) is classified Likely benign in RELN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-20). Very rare (popmax 0.00288%, nfe); Associated with Norman-Roberts syndrome.

What condition is associated with RELN p.Ile1978= (c.5934C>T)?

RELN p.Ile1978= (c.5934C>T) is associated with Norman-Roberts syndrome, familial temporal lobe epilepsy 7 (ClinVar).

How common is RELN p.Ile1978= (c.5934C>T) in the general population?

RELN p.Ile1978= (c.5934C>T) is very rare (popmax 0.00288%, nfe) (gnomAD).

RELN p.Ile1978=

c.5934C>T · rs141509094 · VCV728601

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00288%, nfe)

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	all four deltas below 0.2 · G>T here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.39	GERP -3.8, phastCons 0.64
Overall
CADD	9.73	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00288% European (non-Finnish) · 34/1,179,998 alleles

Filtering AF 0.00207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00235% 38/1,613,950 alleles · very rare exomes 37/1,461,804 · genomes 1/152,146 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00288%	34,706
East Asian	0.00223%	44,876
South Asian	0.0022%	45,539
Remaining individualsnot grpmax-eligible	0.0016%	62,476

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.Ile1978=
Coding: c.5934C>T
MANE Select: NM_005045
dbSNP: rs141509094
Type: single nucleotide variant
Location: chr7:103553695 (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.Ile1978Val 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
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-ile1978 (accessed [today's date]).

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