Is RELN p.Ile494Val (c.1480A>G) pathogenic?

RELN p.Ile494Val (c.1480A>G) is classified Conflicting classifications of pathogenicity in RELN (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-26). AlphaMissense: likely benign (0.07); Ultra-rare (popmax 0.0461%, sas); Associated with Norman-Roberts syndrome.

What condition is associated with RELN p.Ile494Val (c.1480A>G)?

RELN p.Ile494Val (c.1480A>G) is associated with Norman-Roberts syndrome, familial temporal lobe epilepsy 7, epilepsy, familial temporal lobe, 1 (ClinVar).

How common is RELN p.Ile494Val (c.1480A>G) in the general population?

RELN p.Ile494Val (c.1480A>G) is ultra-rare (popmax 0.0461%, sas) (gnomAD).

What do computational predictors say about RELN p.Ile494Val (c.1480A>G)?

AlphaMissense predicts likely benign (score 0.07) — an in-silico prediction, not a clinical call.

RELN p.Ile494Val

c.1480A>G · rs372015884 · VCV965291

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.07 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0461%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Norman-Roberts syndrome

Computational evidence

Protein change
AlphaMissense	0.07	likely benign
REVEL	0.148	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 -1.8	GERP -4
Regional constraint	o/e 0.93	unconstrained · MANE · 432 kb · p 0.0016 · regional, not allelic
Overall
CADD	0.016	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 0.0461% South Asian · 42/91,054 alleles

Filtering AF 0.035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0311%

Overall 0.0036% 58/1,611,696 alleles · ultra-rare exomes 56/1,459,644 · genomes 2/152,052 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0461%	2,168
Remaining individualsnot grpmax-eligible	0.00641%	15,590
European (non-Finnish)	0.00102%	98,198

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.Ile494Val
Coding: c.1480A>G
MANE Select: NM_005045
dbSNP: rs372015884
Type: single nucleotide variant
Location: chr7:103654167 (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 epilepsy, familial temporal lobe, 1

Similar variants

RELN p.Ile494= Conflicting classifications of pathogenicity ★ 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-ile494val (accessed [today's date]).

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