Is RELN p.Pro1675= (c.5025C>T) pathogenic?

RELN p.Pro1675= (c.5025C>T) is classified Conflicting classifications of pathogenicity in RELN (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-25). Ultra-rare (popmax 0.0602%, eas); Associated with Norman-Roberts syndrome.

What condition is associated with RELN p.Pro1675= (c.5025C>T)?

RELN p.Pro1675= (c.5025C>T) is associated with Norman-Roberts syndrome, familial temporal lobe epilepsy 7 (ClinVar).

How common is RELN p.Pro1675= (c.5025C>T) in the general population?

RELN p.Pro1675= (c.5025C>T) is ultra-rare (popmax 0.0602%, eas) (gnomAD).

RELN p.Pro1675=

c.5025C>T · rs748927848 · VCV911433

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0602%, eas)

Conditions

Norman-Roberts syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP -2.6, phastCons 1
Overall
CADD	5.21	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0602% East Asian · 27/44,844 alleles

Filtering AF 0.0424% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0365%

Overall 0.00508% 82/1,613,826 alleles · ultra-rare exomes 69/1,461,604 · genomes 13/152,222 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0704%	1,420
East Asiangrpmax	0.0602%	1,661
African / African-American	0.00667%	15,001
Admixed American	0.005%	19,989
South Asian	0.0022%	45,519
European (non-Finnish)	8.48e-05%	1,179,917

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.Pro1675=
Coding: c.5025C>T
MANE Select: NM_005045
dbSNP: rs748927848
Type: single nucleotide variant
Location: chr7:103565463 (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.Pro1675Ala 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-pro1675 (accessed [today's date]).

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