Is RELN p.Pro2875Arg (c.8624C>G) pathogenic?

RELN p.Pro2875Arg (c.8624C>G) is classified Uncertain significance in RELN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-18). AlphaMissense: likely benign (0.1389); Very rare (popmax 0.00134%, afr); Associated with Norman-Roberts syndrome.

What condition is associated with RELN p.Pro2875Arg (c.8624C>G)?

RELN p.Pro2875Arg (c.8624C>G) is associated with Norman-Roberts syndrome, familial temporal lobe epilepsy 7 (ClinVar).

How common is RELN p.Pro2875Arg (c.8624C>G) in the general population?

RELN p.Pro2875Arg (c.8624C>G) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about RELN p.Pro2875Arg (c.8624C>G)?

AlphaMissense predicts likely benign (score 0.1389) — an in-silico prediction, not a clinical call.

RELN p.Pro2875Arg

c.8624C>G · rs761738403 · VCV1516728

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1389 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

Norman-Roberts syndrome

Computational evidence

Protein change
AlphaMissense	0.1389	likely benign
REVEL	0.292	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 67 kb · p 2.1e-16 · regional, not allelic
Overall
CADD	23.4	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 0.00134% African / African-American · 1/74,876 alleles

Overall 0.000124% 2/1,613,914 alleles · very rare exomes 1/1,461,828 · genomes 1/152,086 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,484
African / African-Americangrpmax	0.00134%	74,876

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.Pro2875Arg
Coding: c.8624C>G
MANE Select: NM_005045
dbSNP: rs761738403
Type: single nucleotide variant
Location: chr7:103500788 (GRCh38)
Gene constraint: LOEUF 0.276 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 2875: the egf-like 7 domain

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.Pro2875Leu Conflicting classifications of pathogenicity ★ ⚠ 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-pro2875arg (accessed [today's date]).

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