Is RELN p.Arg2192Pro (c.6575G>C) pathogenic?

RELN p.Arg2192Pro (c.6575G>C) is classified Uncertain significance in RELN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-09-22). AlphaMissense: likely pathogenic (0.9322); Very rare (popmax 0.0011%, sas); Associated with Norman-Roberts syndrome.

What condition is associated with RELN p.Arg2192Pro (c.6575G>C)?

RELN p.Arg2192Pro (c.6575G>C) is associated with Norman-Roberts syndrome, familial temporal lobe epilepsy 7 (ClinVar).

How common is RELN p.Arg2192Pro (c.6575G>C) in the general population?

RELN p.Arg2192Pro (c.6575G>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about RELN p.Arg2192Pro (c.6575G>C)?

AlphaMissense predicts likely pathogenic (score 0.9322) — an in-silico prediction, not a clinical call.

RELN p.Arg2192Pro

c.6575G>C · rs1309424440 · VCV1001415

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9322 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Norman-Roberts syndrome

Computational evidence

Protein change
AlphaMissense	0.9322	likely pathogenic
REVEL	0.283	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 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 67 kb · p 2.1e-16 · regional, not allelic
Overall
CADD	25.5	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 0.0011% South Asian · 1/91,072 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000496% 8/1,613,904 alleles · very rare exomes 7/1,461,804 · genomes 1/152,100 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,072
European (non-Finnish)	0.000593%	168,568

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.Arg2192Pro
Coding: c.6575G>C
MANE Select: NM_005045
dbSNP: rs1309424440
Type: single nucleotide variant
Location: chr7:103542827 (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.Arg2192Ter Pathogenic ★ same residue
RELN p.Arg2192= Uncertain significance ★ same residue
RELN p.Arg2192Gln 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

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-arg2192pro (accessed [today's date]).

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