Is RELN p.Phe3439Ser (c.10316T>C) pathogenic?

RELN p.Phe3439Ser (c.10316T>C) is classified Uncertain significance in RELN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-06). AlphaMissense: ambiguous (0.5528); Very rare (popmax 8.48e-05%, nfe); Associated with Norman-Roberts syndrome.

What condition is associated with RELN p.Phe3439Ser (c.10316T>C)?

RELN p.Phe3439Ser (c.10316T>C) is associated with Norman-Roberts syndrome, familial temporal lobe epilepsy 7 (ClinVar).

How common is RELN p.Phe3439Ser (c.10316T>C) in the general population?

RELN p.Phe3439Ser (c.10316T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about RELN p.Phe3439Ser (c.10316T>C)?

AlphaMissense predicts ambiguous (score 0.5528) — an in-silico prediction, not a clinical call.

RELN p.Phe3439Ser

c.10316T>C · VCV4783056

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5528 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

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
AlphaMissense	0.5528	ambiguous
REVEL	0.659	pathogenic-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 17 kb · p 2.7e-07 · regional, not allelic
Overall
CADD	26.3	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 8.48e-05% European (non-Finnish) · 1/1,179,868 alleles

Overall 6.2e-05% 1/1,613,988 alleles · very rare exomes 1/1,461,656 · genomes 0/152,332 · 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.Phe3439Ser
Coding: c.10316T>C
MANE Select: NM_005045
Type: single nucleotide variant
Location: chr7:103472879 (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-phe3439ser (accessed [today's date]).

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