Is RELN p.Ser281Arg (c.843C>A) pathogenic?

RELN p.Ser281Arg (c.843C>A) is classified Uncertain significance in RELN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-12). AlphaMissense: ambiguous (0.4091); No allele count reported in gnomAD v4.1 (AN 1,612,176); Associated with Norman-Roberts syndrome.

What condition is associated with RELN p.Ser281Arg (c.843C>A)?

RELN p.Ser281Arg (c.843C>A) is associated with Norman-Roberts syndrome, familial temporal lobe epilepsy 7 (ClinVar).

How common is RELN p.Ser281Arg (c.843C>A) in the general population?

RELN p.Ser281Arg (c.843C>A) is no allele count reported in gnomAD v4.1 (AN 1,612,176) (gnomAD).

What do computational predictors say about RELN p.Ser281Arg (c.843C>A)?

AlphaMissense predicts ambiguous (score 0.4091) — an in-silico prediction, not a clinical call.

RELN p.Ser281Arg

c.843C>A · rs1277811940 · VCV2952052

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4091 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,612,176)

Conditions

Norman-Roberts syndrome

Computational evidence

Protein change
AlphaMissense	0.4091	ambiguous
REVEL	0.087	moderately benign-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 0.85, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 432 kb · p 0.0016 · regional, not allelic
Overall
CADD	19.24	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

No allele count reported in gnomAD v4.1 (AN 1,612,176). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: RELN
Protein: p.Ser281Arg
Coding: c.843C>A
MANE Select: NM_005045
dbSNP: rs1277811940
Type: single nucleotide variant
Location: chr7:103700969 (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

Similar variants

RELN p.Ser281= Likely benign ★ 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-ser281arg (accessed [today's date]).

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