Is RELN p.Thr139Ser (c.416C>G) pathogenic?

RELN p.Thr139Ser (c.416C>G) is classified Benign in RELN (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.1566); Common (popmax 7.18%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Norman-Roberts syndrome.

What condition is associated with RELN p.Thr139Ser (c.416C>G)?

RELN p.Thr139Ser (c.416C>G) is associated with Norman-Roberts syndrome, familial temporal lobe epilepsy 7, epilepsy, familial temporal lobe, 1 (ClinVar).

What do computational predictors say about RELN p.Thr139Ser (c.416C>G)?

AlphaMissense predicts likely benign (score 0.1566) — an in-silico prediction, not a clinical call.

RELN p.Thr139Ser

Q: How common is RELN p.Thr139Ser (c.416C>G) in the general population?

RELN p.Thr139Ser (c.416C>G) is common (popmax 7.18%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.416C>G · rs79471015 · VCV130121

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1566 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 7.18%, eas) — 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	0.1566	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 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 432 kb · p 0.0016 · regional, not allelic
Overall
CADD	24.3	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 7.18% East Asian · 3,221/44,846 alleles

Filtering AF 6.98% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.89%

Overall 0.312% 5,039/1,613,960 alleles · common exomes 4,476/1,461,672 · genomes 563/152,288 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	7.18%	14
Admixed American	1.97%	51
Remaining individualsnot grpmax-eligible	0.258%	388
Middle Eastern	0.099%	1,010
South Asian	0.0944%	1,059
Ashkenazi Jewishnot grpmax-eligible	0.0912%	1,096
African / African-American	0.056%	1,786
European (non-Finnish)	0.0268%	3,734

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.Thr139Ser
Coding: c.416C>G
MANE Select: NM_005045
dbSNP: rs79471015
Type: single nucleotide variant
Location: chr7:103833594 (GRCh38)
Gene constraint: LOEUF 0.276 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 139: the reelin domain

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 p.Thr139Ile Uncertain significance ★★ same residue
RELN p.Thr139Ala 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
RELN c.227-3C>T Uncertain significance ★★ same condition
RELN c.2465+5G>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-thr139ser (accessed [today's date]).

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