Is RELN p.Arg730His (c.2189G>A) pathogenic?

RELN p.Arg730His (c.2189G>A) is classified Uncertain significance in RELN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-01). AlphaMissense: likely benign (0.1027); Very rare (popmax 0.00678%, nfe); Associated with familial temporal lobe epilepsy 7.

What condition is associated with RELN p.Arg730His (c.2189G>A)?

RELN p.Arg730His (c.2189G>A) is associated with familial temporal lobe epilepsy 7, Norman-Roberts syndrome (ClinVar).

How common is RELN p.Arg730His (c.2189G>A) in the general population?

RELN p.Arg730His (c.2189G>A) is very rare (popmax 0.00678%, nfe) (gnomAD).

What do computational predictors say about RELN p.Arg730His (c.2189G>A)?

AlphaMissense predicts likely benign (score 0.1027) — an in-silico prediction, not a clinical call.

RELN p.Arg730His

c.2189G>A · rs370858334 · VCV855266

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1027 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00678%, nfe)

Conditions

familial temporal lobe epilepsy 7

Computational evidence

Protein change
AlphaMissense	0.1027	likely benign
REVEL	0.369	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 432 kb · p 0.0016 · regional, not allelic
Overall
CADD	26.2	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 0.00678% European (non-Finnish) · 80/1,179,890 alleles

Filtering AF 0.00555% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00514%

Overall 0.00539% 87/1,613,760 alleles · very rare exomes 83/1,461,662 · genomes 4/152,098 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00678%	14,749
Remaining individualsnot grpmax-eligible	0.0048%	20,827
African / African-American	0.00401%	24,963
South Asian	0.0011%	91,082

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.Arg730His
Coding: c.2189G>A
MANE Select: NM_005045
dbSNP: rs370858334
Type: single nucleotide variant
Location: chr7:103636349 (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

familial temporal lobe epilepsy 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Norman-Roberts syndrome

Similar variants

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
RELN c.6072+4C>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-arg730his (accessed [today's date]).

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