Is SCN2A p.Pro37Arg (c.110C>G) pathogenic?

SCN2A p.Pro37Arg (c.110C>G) is classified Uncertain significance in SCN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-02). AlphaMissense: likely benign (0.1317); Absent from gnomAD v4.1; Associated with developmental and epileptic encephalopathy, 11.

What condition is associated with SCN2A p.Pro37Arg (c.110C>G)?

SCN2A p.Pro37Arg (c.110C>G) is associated with developmental and epileptic encephalopathy, 11, seizures, benign familial infantile, 3 (ClinVar).

How common is SCN2A p.Pro37Arg (c.110C>G) in the general population?

SCN2A p.Pro37Arg (c.110C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SCN2A p.Pro37Arg (c.110C>G)?

AlphaMissense predicts likely benign (score 0.1317) — an in-silico prediction, not a clinical call.

SCN2A p.Pro37Arg

c.110C>G · rs2467838210 · VCV2950505

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1317 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

developmental and epileptic encephalopathy, 11

Computational evidence

Protein change
AlphaMissense	0.1317	likely benign
REVEL	0.493	indeterminate
SaProt	LLR -4.68	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 6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 12 kb · p 0.0011 · regional, not allelic
Overall
CADD	25.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SCN2A
Protein: p.Pro37Arg
Coding: c.110C>G
MANE Select: NM_001040142
dbSNP: rs2467838210
Type: single nucleotide variant
Location: chr2:165295933 (GRCh38)
Gene constraint: LOEUF 0.161 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 69.28 · 5 PDB
Residue 37: 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.Pro37Leu Uncertain significance ★ ⚠ same residue
SCN2A p.Pro37Thr 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-pro37arg (accessed [today's date]).

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