Is RELN p.Ser600Phe (c.1799C>T) pathogenic?

RELN p.Ser600Phe (c.1799C>T) is classified Benign/Likely benign in RELN (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-07-01). AlphaMissense: likely benign (0.2723); Low-frequency (popmax 1.63%, nfe); Associated with Norman-Roberts syndrome.

What condition is associated with RELN p.Ser600Phe (c.1799C>T)?

RELN p.Ser600Phe (c.1799C>T) is associated with Norman-Roberts syndrome, familial temporal lobe epilepsy 7, epilepsy, familial temporal lobe, 1 (ClinVar).

How common is RELN p.Ser600Phe (c.1799C>T) in the general population?

RELN p.Ser600Phe (c.1799C>T) is low-frequency (popmax 1.63%, nfe) (gnomAD).

What do computational predictors say about RELN p.Ser600Phe (c.1799C>T)?

AlphaMissense predicts likely benign (score 0.2723) — an in-silico prediction, not a clinical call.

RELN p.Ser600Phe

c.1799C>T · rs78008536 · VCV95213

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.2723 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.63%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Norman-Roberts syndrome

Computational evidence

Protein change
AlphaMissense	0.2723	likely benign
REVEL	0.207	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 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 432 kb · p 0.0016 · regional, not allelic
Overall
CADD	24.8	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 1.63% European (non-Finnish) · 19,254/1,178,636 alleles

Filtering AF 1.61% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.61%

Overall 1.4% 22,506/1,611,790 alleles · low-frequency exomes 20,911/1,459,774 · genomes 1,595/152,016 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.79%	56
European (non-Finnish)grpmax	1.63%	61
Ashkenazi Jewishnot grpmax-eligible	1.05%	95
Remaining individualsnot grpmax-eligible	1.05%	95
South Asian	0.777%	129
Admixed American	0.438%	228
Middle Eastern	0.281%	355
African / African-American	0.212%	471
East Asian	0.00224%	44,726

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.Ser600Phe
Coding: c.1799C>T
MANE Select: NM_005045
dbSNP: rs78008536
Type: single nucleotide variant
Location: chr7:103651754 (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 epilepsy, familial temporal lobe, 1

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-ser600phe (accessed [today's date]).

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