Is RELN p.Gln9Pro (c.26A>C) pathogenic?

RELN p.Gln9Pro (c.26A>C) is classified Benign/Likely benign in RELN (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0637); Common (popmax 7.75%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Norman-Roberts syndrome.

What condition is associated with RELN p.Gln9Pro (c.26A>C)?

RELN p.Gln9Pro (c.26A>C) is associated with Norman-Roberts syndrome, familial temporal lobe epilepsy 7 (ClinVar).

What do computational predictors say about RELN p.Gln9Pro (c.26A>C)?

AlphaMissense predicts likely benign (score 0.0637) — an in-silico prediction, not a clinical call.

RELN p.Gln9Pro

Q: How common is RELN p.Gln9Pro (c.26A>C) in the general population?

RELN p.Gln9Pro (c.26A>C) is common (popmax 7.75%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.26A>C · rs115165703 · VCV95217

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0637 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 7.75%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Norman-Roberts syndrome

Computational evidence

Protein change
AlphaMissense	0.0637	likely benign
REVEL	0.04	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP -0.22, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 432 kb · p 0.0016 · regional, not allelic
Overall
CADD	18.79	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 7.75% African / African-American · 5,631/72,694 alleles

Filtering AF 7.58% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.51%

Overall 0.402% 6,338/1,576,612 alleles · common exomes 3,064/1,427,204 · genomes 3,274/149,408 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	7.75%	13
Admixed American	0.524%	191
Middle Eastern	0.496%	201
Remaining individualsnot grpmax-eligible	0.488%	205
South Asian	0.0147%	6,791
European (non-Finnish)	0.00544%	18,387

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.Gln9Pro
Coding: c.26A>C
MANE Select: NM_005045
dbSNP: rs115165703
Type: single nucleotide variant
Location: chr7:103989331 (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.Gln9Glu Uncertain significance ★ ⚠ same residue
RELN p.Gln9Arg Likely benign ★ same residue
RELN p.Gln9Ter Likely pathogenic ★ same residue
RELN p.Gln9Leu 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

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-gln9pro (accessed [today's date]).

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