Is RELN p.Arg2011Cys (c.6031C>T) pathogenic?

RELN p.Arg2011Cys (c.6031C>T) is classified Uncertain significance in RELN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-05-15). AlphaMissense: likely pathogenic (0.6758); Very rare (popmax 0.005%, amr); Associated with familial temporal lobe epilepsy 7.

What condition is associated with RELN p.Arg2011Cys (c.6031C>T)?

RELN p.Arg2011Cys (c.6031C>T) is associated with familial temporal lobe epilepsy 7, Norman-Roberts syndrome (ClinVar).

How common is RELN p.Arg2011Cys (c.6031C>T) in the general population?

RELN p.Arg2011Cys (c.6031C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about RELN p.Arg2011Cys (c.6031C>T)?

AlphaMissense predicts likely pathogenic (score 0.6758) — an in-silico prediction, not a clinical call.

RELN p.Arg2011Cys

c.6031C>T · rs374628146 · VCV475975

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6758 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

familial temporal lobe epilepsy 7

Computational evidence

Protein change
AlphaMissense	0.6758	likely pathogenic
REVEL	0.26	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 67 kb · p 2.1e-16 · regional, not allelic
Overall
CADD	25.1	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 0.005% Admixed American · 3/60,018 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00161% 26/1,613,908 alleles · very rare exomes 21/1,461,624 · genomes 5/152,284 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,006
African / African-American	0.00267%	37,519
East Asian	0.00223%	44,860
South Asian	0.0022%	45,539
European (non-Finnish)	0.00153%	65,546

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.Arg2011Cys
Coding: c.6031C>T
MANE Select: NM_005045
dbSNP: rs374628146
Type: single nucleotide variant
Location: chr7:103553502 (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 p.Arg2011His Likely benign ★ same residue
RELN p.Arg2011Ser 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

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-arg2011cys (accessed [today's date]).

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