Is RELN p.Ile2128Phe (c.6382A>T) pathogenic?

RELN p.Ile2128Phe (c.6382A>T) is classified Uncertain significance in RELN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-24). AlphaMissense: ambiguous (0.5294); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with RELN p.Ile2128Phe (c.6382A>T)?

RELN p.Ile2128Phe (c.6382A>T) is associated with Inborn genetic diseases (ClinVar).

How common is RELN p.Ile2128Phe (c.6382A>T) in the general population?

RELN p.Ile2128Phe (c.6382A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RELN p.Ile2128Phe (c.6382A>T)?

AlphaMissense predicts ambiguous (score 0.5294) — an in-silico prediction, not a clinical call.

RELN p.Ile2128Phe

c.6382A>T · VCV3788183

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5294 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5294	ambiguous
REVEL	0.263	benign-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.2	GERP -4.2, phastCons 0.99
Regional constraint	o/e 0.80	unconstrained · MANE · 67 kb · p 2.1e-16 · regional, not allelic
Overall
CADD	20.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RELN
Protein: p.Ile2128Phe
Coding: c.6382A>T
MANE Select: NM_005045
Type: single nucleotide variant
Location: chr7:103545265 (GRCh38)
Gene constraint: LOEUF 0.276 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 2128: the egf-like 5 domain

Full RELN gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RELN p.Ile2128= Likely benign ★★ same residue
RELN p.Ile2128Val Likely benign ★ same residue
RELN p.Ala1272Val Uncertain significance ★★ ⚠ same condition
RELN p.Ala1651Ser Uncertain significance ★★ same condition
RELN p.Ala1823Glu Uncertain significance ★★ same condition
RELN p.Ala2742Val Uncertain significance ★★ ⚠ same condition
RELN p.Ala2937Thr Uncertain significance ★★ ⚠ same condition
RELN p.Ala787Ser 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-ile2128phe (accessed [today's date]).

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