Is RELN p.Pro1066= (c.3198G>A) pathogenic?

RELN p.Pro1066= (c.3198G>A) is classified Likely benign in RELN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-20). Ultra-rare (popmax 0.0167%, amr); Associated with familial temporal lobe epilepsy 7.

What condition is associated with RELN p.Pro1066= (c.3198G>A)?

RELN p.Pro1066= (c.3198G>A) is associated with familial temporal lobe epilepsy 7, Norman-Roberts syndrome (ClinVar).

How common is RELN p.Pro1066= (c.3198G>A) in the general population?

RELN p.Pro1066= (c.3198G>A) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

RELN p.Pro1066=

c.3198G>A · rs767180170 · VCV702840

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Conditions

familial temporal lobe epilepsy 7

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 0.65	GERP -3.1, phastCons 0.94
Overall
CADD	8.745	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% Admixed American · 10/59,966 alleles

Filtering AF 0.0105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00995%

Overall 0.0106% 171/1,613,762 alleles · ultra-rare exomes 162/1,461,632 · genomes 9/152,130 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	5,997
Middle Eastern	0.0164%	6,080
European (non-Finnish)	0.0122%	8,193
Remaining individualsnot grpmax-eligible	0.0096%	10,412
African / African-American	0.00801%	12,483
East Asian	0.00446%	22,430
South Asian	0.0022%	45,546

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.Pro1066=
Coding: c.3198G>A
MANE Select: NM_005045
dbSNP: rs767180170
Type: single nucleotide variant
Location: chr7:103603439 (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

familial temporal lobe epilepsy 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Norman-Roberts syndrome

Similar variants

RELN p.Pro1066Leu Conflicting classifications of pathogenicity ★ ⚠ 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-pro1066 (accessed [today's date]).

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