Is RELN p.Arg3431His (c.10292G>A) pathogenic?

RELN p.Arg3431His (c.10292G>A) is classified Uncertain significance in RELN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-18). AlphaMissense: likely pathogenic (0.5998); Very rare (popmax 0.00356%, nfe); Associated with Norman-Roberts syndrome.

What condition is associated with RELN p.Arg3431His (c.10292G>A)?

RELN p.Arg3431His (c.10292G>A) is associated with Norman-Roberts syndrome, familial temporal lobe epilepsy 7 (ClinVar).

How common is RELN p.Arg3431His (c.10292G>A) in the general population?

RELN p.Arg3431His (c.10292G>A) is very rare (popmax 0.00356%, nfe) (gnomAD).

What do computational predictors say about RELN p.Arg3431His (c.10292G>A)?

AlphaMissense predicts likely pathogenic (score 0.5998) — an in-silico prediction, not a clinical call.

RELN p.Arg3431His

c.10292G>A · rs1442266027 · VCV1507711

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.5998 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00356%, nfe)

Conditions

Norman-Roberts syndrome

Computational evidence

Protein change
AlphaMissense	0.5998	likely pathogenic
REVEL	0.638	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 17 kb · p 2.7e-07 · regional, not allelic
Overall
CADD	29.0	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 0.00356% European (non-Finnish) · 42/1,179,404 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.00298% 48/1,613,118 alleles · very rare exomes 47/1,461,144 · genomes 1/151,974 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00801%	12,490
European (non-Finnish)grpmax	0.00356%	28,081
South Asian	0.0011%	91,058

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg3431His
Coding: c.10292G>A
MANE Select: NM_005045
dbSNP: rs1442266027
Type: single nucleotide variant
Location: chr7:103472903 (GRCh38)
Gene constraint: LOEUF 0.276 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 3431: an α-helix

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 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-arg3431his (accessed [today's date]).

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