Is RELN p.Leu997Phe (c.2989C>T) pathogenic?

RELN p.Leu997Phe (c.2989C>T) is classified Conflicting classifications of pathogenicity in RELN (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.1032); Ultra-rare (popmax 0.0108%, afr); Associated with familial temporal lobe epilepsy 7.

What condition is associated with RELN p.Leu997Phe (c.2989C>T)?

RELN p.Leu997Phe (c.2989C>T) is associated with familial temporal lobe epilepsy 7, Norman-Roberts syndrome (ClinVar).

How common is RELN p.Leu997Phe (c.2989C>T) in the general population?

RELN p.Leu997Phe (c.2989C>T) is ultra-rare (popmax 0.0108%, afr) (gnomAD).

What do computational predictors say about RELN p.Leu997Phe (c.2989C>T)?

AlphaMissense predicts likely benign (score 0.1032) — an in-silico prediction, not a clinical call.

RELN p.Leu997Phe

c.2989C>T · rs362691 · VCV475955

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1032 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0108%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

familial temporal lobe epilepsy 7

Computational evidence

Protein change
AlphaMissense	0.1032	likely benign
REVEL	0.074	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 7.5	GERP 2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 432 kb · p 0.0016 · regional, not allelic
Overall
CADD	20.8	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 0.0108% African / African-American · 8/74,208 alleles

Filtering AF 0.00532% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00384%

Overall 0.00101% 16/1,583,628 alleles · ultra-rare exomes 14/1,431,562 · genomes 2/152,066 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0108%	9,276
Remaining individualsnot grpmax-eligible	0.00976%	10,247
Admixed American	0.00167%	59,954
European (non-Finnish)	8.67e-05%	1,152,794

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.Leu997Phe
Coding: c.2989C>T
MANE Select: NM_005045
dbSNP: rs362691
Type: single nucleotide variant
Location: chr7:103610714 (GRCh38)
Gene constraint: LOEUF 0.276 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 997: a UniProt-annotated variant site (in)

Full RELN gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial temporal lobe epilepsy 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Norman-Roberts syndrome

Similar variants

RELN p.Leu997Val Benign ★★ 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-leu997phe (accessed [today's date]).

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