Is RELN p.Pro1703Arg (c.5108C>G) pathogenic?

RELN p.Pro1703Arg (c.5108C>G) is classified Conflicting classifications of pathogenicity in RELN (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-04-01). AlphaMissense: likely pathogenic (0.9354); Rare (popmax 0.527%, nfe); Associated with Norman-Roberts syndrome.

What condition is associated with RELN p.Pro1703Arg (c.5108C>G)?

RELN p.Pro1703Arg (c.5108C>G) is associated with Norman-Roberts syndrome, familial temporal lobe epilepsy 7 (ClinVar).

How common is RELN p.Pro1703Arg (c.5108C>G) in the general population?

RELN p.Pro1703Arg (c.5108C>G) is rare (popmax 0.527%, nfe) (gnomAD).

What do computational predictors say about RELN p.Pro1703Arg (c.5108C>G)?

AlphaMissense predicts likely pathogenic (score 0.9354) — an in-silico prediction, not a clinical call.

RELN p.Pro1703Arg

c.5108C>G · rs2229860 · VCV130125

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

likely pathogenic

0.9354 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.527%, nfe)

Conditions

Norman-Roberts syndrome

Computational evidence

Protein change
AlphaMissense	0.9354	likely pathogenic
REVEL	0.481	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 432 kb · p 0.0016 · regional, not allelic
Overall
CADD	26.9	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 0.527% European (non-Finnish) · 6,213/1,179,970 alleles

Filtering AF 0.516% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.511%

Overall 0.446% 7,191/1,614,054 alleles · rare exomes 6,656/1,461,804 · genomes 535/152,250 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.667%	150
European (non-Finnish)grpmax	0.527%	190
Remaining individualsnot grpmax-eligible	0.379%	264
Admixed American	0.21%	476
Ashkenazi Jewishnot grpmax-eligible	0.118%	846
Amishnot grpmax-eligible	0.11%	912
South Asian	0.105%	949
African / African-American	0.072%	1,389
Middle Eastern	0.033%	3,030

Finnish 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.Pro1703Arg
Coding: c.5108C>G
MANE Select: NM_005045
dbSNP: rs2229860
Type: single nucleotide variant
Location: chr7:103565380 (GRCh38)
Gene constraint: LOEUF 0.276 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 1703: a UniProt-annotated variant site (in)

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-pro1703arg (accessed [today's date]).

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