Is RELN p.Arg2242Ser (c.6726G>C) pathogenic?

RELN p.Arg2242Ser (c.6726G>C) is classified Conflicting classifications of pathogenicity in RELN (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-02-02). AlphaMissense: likely pathogenic (0.8025); Rare (popmax 0.158%, amr); Associated with Norman-Roberts syndrome.

What condition is associated with RELN p.Arg2242Ser (c.6726G>C)?

RELN p.Arg2242Ser (c.6726G>C) is associated with Norman-Roberts syndrome, familial temporal lobe epilepsy 7, epilepsy, familial temporal lobe, 1 (ClinVar).

How common is RELN p.Arg2242Ser (c.6726G>C) in the general population?

RELN p.Arg2242Ser (c.6726G>C) is rare (popmax 0.158%, amr) (gnomAD).

What do computational predictors say about RELN p.Arg2242Ser (c.6726G>C)?

AlphaMissense predicts likely pathogenic (score 0.8025) — an in-silico prediction, not a clinical call.

RELN p.Arg2242Ser

c.6726G>C · rs201422815 · VCV130135

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.8025 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.158%, amr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Norman-Roberts syndrome

Computational evidence

Protein change
AlphaMissense	0.8025	likely pathogenic
REVEL	0.188	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 0.59	GERP -1.1, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 67 kb · p 2.1e-16 · regional, not allelic
Overall
CADD	21.1	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 0.158% Admixed American · 95/59,994 alleles

Filtering AF 0.133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.123%

Overall 0.0114% 184/1,613,982 alleles · rare exomes 155/1,461,842 · genomes 29/152,140 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.158%	632
Remaining individualsnot grpmax-eligible	0.0256%	3,905
European (non-Finnish)	0.0061%	16,389
African / African-American	0.00133%	74,912

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.Arg2242Ser
Coding: c.6726G>C
MANE Select: NM_005045
dbSNP: rs201422815
Type: single nucleotide variant
Location: chr7:103540401 (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.Arg2242Met 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-arg2242ser (accessed [today's date]).

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