Is RELN p.Ile650Phe (c.1948A>T) pathogenic?

RELN p.Ile650Phe (c.1948A>T) is classified Uncertain significance in RELN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-13). AlphaMissense: likely benign (0.0878); Very rare (popmax 0.000848%, nfe); Associated with Norman-Roberts syndrome.

What condition is associated with RELN p.Ile650Phe (c.1948A>T)?

RELN p.Ile650Phe (c.1948A>T) is associated with Norman-Roberts syndrome, familial temporal lobe epilepsy 7 (ClinVar).

How common is RELN p.Ile650Phe (c.1948A>T) in the general population?

RELN p.Ile650Phe (c.1948A>T) is very rare (popmax 0.000848%, nfe) (gnomAD).

What do computational predictors say about RELN p.Ile650Phe (c.1948A>T)?

AlphaMissense predicts likely benign (score 0.0878) — an in-silico prediction, not a clinical call.

RELN p.Ile650Phe

c.1948A>T · rs371652596 · VCV547025

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0878 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000848%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Norman-Roberts syndrome

Computational evidence

Protein change
AlphaMissense	0.0878	likely benign
REVEL	0.119	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP 2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 432 kb · p 0.0016 · regional, not allelic
Overall
CADD	17.38	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000848% European (non-Finnish) · 10/1,179,434 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.00062% 10/1,613,048 alleles · very rare exomes 6/1,460,942 · genomes 4/152,106 · 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.Ile650Phe
Coding: c.1948A>T
MANE Select: NM_005045
dbSNP: rs371652596
Type: single nucleotide variant
Location: chr7:103650328 (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.Ile650Val 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-ile650phe (accessed [today's date]).

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