Is SCN2A p.Pro151Ser (c.451C>T) pathogenic?

SCN2A p.Pro151Ser (c.451C>T) is classified Uncertain significance in SCN2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-09). AlphaMissense: likely pathogenic (0.8725); Very rare (popmax 0.000936%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SCN2A p.Pro151Ser (c.451C>T)?

SCN2A p.Pro151Ser (c.451C>T) is associated with Inborn genetic diseases, developmental and epileptic encephalopathy, 11 (ClinVar).

How common is SCN2A p.Pro151Ser (c.451C>T) in the general population?

SCN2A p.Pro151Ser (c.451C>T) is very rare (popmax 0.000936%, nfe) (gnomAD).

What do computational predictors say about SCN2A p.Pro151Ser (c.451C>T)?

AlphaMissense predicts likely pathogenic (score 0.8725) — an in-silico prediction, not a clinical call.

SCN2A p.Pro151Ser

c.451C>T · rs200109956 · VCV982644

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8725 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000936%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8725	likely pathogenic
REVEL	0.782	moderately pathogenic-leaning
SaProt	LLR -14.22	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 12 kb · p 0.0011 · regional, not allelic
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000936% European (non-Finnish) · 11/1,175,278 alleles

Filtering AF 0.000502% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000367%

Overall 0.000684% 11/1,608,582 alleles · very rare

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: SCN2A
Protein: p.Pro151Ser
Coding: c.451C>T
MANE Select: NM_001040142
dbSNP: rs200109956
Type: single nucleotide variant
Location: chr2:165307912 (GRCh38)
Gene constraint: LOEUF 0.161 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 69.28 · 5 PDB
Residue 151: a UniProt-annotated variant site (found in a patient with intractable epilepsy and severe mental decline; likely pathogenic; non-conducting; loss of voltage-gated sodium channel activity; dominant-negative)

Full SCN2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: developmental and epileptic encephalopathy, 11

Similar variants

SCN2A p.Pro151fs Pathogenic ★ same residue
SCN2A p.Pro151Ala Uncertain significance ★ ⚠ same residue
SCN2A p.Ala1773Thr Pathogenic ★★★ same condition
SCN2A p.Arg220Gly Likely pathogenic ★★★ same condition
SCN2A p.Arg853Gln Pathogenic ★★★ same condition
SCN2A p.Gly899Asp Likely pathogenic ★★★ same condition
SCN2A p.Leu1611Pro Pathogenic ★★★ same condition
SCN2A p.Leu886Ser Likely pathogenic ★★★ 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/scn2a-p-pro151ser (accessed [today's date]).

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