Is RELN p.Pro1236Ser (c.3706C>T) pathogenic?

RELN p.Pro1236Ser (c.3706C>T) is classified Uncertain significance in RELN (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-24). AlphaMissense: ambiguous (0.4351); Very rare (popmax 0.00187%, nfe); Associated with familial temporal lobe epilepsy 7.

What condition is associated with RELN p.Pro1236Ser (c.3706C>T)?

RELN p.Pro1236Ser (c.3706C>T) is associated with familial temporal lobe epilepsy 7, Norman-Roberts syndrome (ClinVar).

How common is RELN p.Pro1236Ser (c.3706C>T) in the general population?

RELN p.Pro1236Ser (c.3706C>T) is very rare (popmax 0.00187%, nfe) (gnomAD).

What do computational predictors say about RELN p.Pro1236Ser (c.3706C>T)?

AlphaMissense predicts ambiguous (score 0.4351) — an in-silico prediction, not a clinical call.

RELN p.Pro1236Ser

c.3706C>T · rs750302438 · VCV542567

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4351 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00187%, nfe)

Conditions

familial temporal lobe epilepsy 7

Computational evidence

Protein change
AlphaMissense	0.4351	ambiguous
REVEL	0.394	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 432 kb · p 0.0016 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00187% European (non-Finnish) · 22/1,179,594 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00149% 24/1,613,452 alleles · very rare exomes 22/1,461,382 · genomes 2/152,070 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00187%	53,618
Remaining individualsnot grpmax-eligible	0.0016%	62,446
African / African-American	0.00134%	74,878

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.Pro1236Ser
Coding: c.3706C>T
MANE Select: NM_005045
dbSNP: rs750302438
Type: single nucleotide variant
Location: chr7:103594326 (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.Pro1236Arg Uncertain significance ★ same residue
RELN p.Pro1236= 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

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-pro1236ser (accessed [today's date]).

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