Is SCN2A p.Pro1981Arg (c.5942C>G) pathogenic?

SCN2A p.Pro1981Arg (c.5942C>G) is classified Uncertain significance in SCN2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-08-31). AlphaMissense: likely benign (0.2367); Very rare (popmax 0.000339%, nfe); Associated with developmental and epileptic encephalopathy, 11.

How common is SCN2A p.Pro1981Arg (c.5942C>G) in the general population?

SCN2A p.Pro1981Arg (c.5942C>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about SCN2A p.Pro1981Arg (c.5942C>G)?

AlphaMissense predicts likely benign (score 0.2367) — an in-silico prediction, not a clinical call.

SCN2A p.Pro1981Arg

Q: What condition is associated with SCN2A p.Pro1981Arg (c.5942C>G)?

SCN2A p.Pro1981Arg (c.5942C>G) is associated with developmental and epileptic encephalopathy, 11, seizures, benign familial infantile, 3 (ClinVar).

c.5942C>G · rs752211376 · VCV1318678

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2367 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

developmental and epileptic encephalopathy, 11

Computational evidence

Protein change
AlphaMissense	0.2367	likely benign
REVEL	0.447	indeterminate
SaProt	LLR -7.98	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 344 bp · p 0.014 · regional, not allelic
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000339% European (non-Finnish) · 4/1,179,684 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,018 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.Pro1981Arg
Coding: c.5942C>G
MANE Select: NM_001040142
dbSNP: rs752211376
Type: single nucleotide variant
Location: chr2:165389748 (GRCh38)
Gene constraint: LOEUF 0.161 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 69.28 · 5 PDB
Residue 1981: 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); a UniProt-annotated variant site (found in a patient with schizofrenia; uncertain significance); a UniProt-annotated variant site (found in a patient with autism spectrum disorder; likely pathogenic); a UniProt-annotated variant site (found in a patient with autism spectrum disorder; likely pathogenic; loss of voltage-gated sodium channel activity; non-conducting); a UniProt-annotated variant site (in dee11); the 'disordered' region

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

Disease context

developmental and epileptic encephalopathy, 11 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: seizures, benign familial infantile, 3

Similar variants

SCN2A p.Pro1981Leu 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
SCN2A p.Lys1260Glu 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-pro1981arg (accessed [today's date]).

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