Is RELN p.Pro3393Ser (c.10177C>T) pathogenic?

RELN p.Pro3393Ser (c.10177C>T) is classified Uncertain significance in RELN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-12). AlphaMissense: likely pathogenic (0.9748); Very rare (popmax 8.47e-05%, nfe); Associated with familial temporal lobe epilepsy 7.

What condition is associated with RELN p.Pro3393Ser (c.10177C>T)?

RELN p.Pro3393Ser (c.10177C>T) is associated with familial temporal lobe epilepsy 7, Norman-Roberts syndrome (ClinVar).

How common is RELN p.Pro3393Ser (c.10177C>T) in the general population?

RELN p.Pro3393Ser (c.10177C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about RELN p.Pro3393Ser (c.10177C>T)?

AlphaMissense predicts likely pathogenic (score 0.9748) — an in-silico prediction, not a clinical call.

RELN p.Pro3393Ser

c.10177C>T · rs771869485 · VCV660465

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9748 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

familial temporal lobe epilepsy 7

⚠ 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
AlphaMissense	0.9748	likely pathogenic
REVEL	0.648	pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 17 kb · p 2.7e-07 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,942 alleles

Overall 6.2e-05% 1/1,613,904 alleles · very rare exomes 0/1,461,790 · genomes 1/152,114 · joint denominator

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.Pro3393Ser
Coding: c.10177C>T
MANE Select: NM_005045
dbSNP: rs771869485
Type: single nucleotide variant
Location: chr7:103483657 (GRCh38)

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

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-pro3393ser (accessed [today's date]).

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