Is SCN2A p.Pro727Ser (c.2179C>T) pathogenic?

SCN2A p.Pro727Ser (c.2179C>T) is classified Uncertain significance in SCN2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-05). AlphaMissense: likely benign (0.3265); Absent from gnomAD v4.1.

How common is SCN2A p.Pro727Ser (c.2179C>T) in the general population?

SCN2A p.Pro727Ser (c.2179C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SCN2A p.Pro727Ser (c.2179C>T)?

AlphaMissense predicts likely benign (score 0.3265) — an in-silico prediction, not a clinical call.

SCN2A p.Pro727Ser

c.2179C>T · rs1339703326 · VCV1694972

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3265 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3265	likely benign
REVEL	0.632	indeterminate
SaProt	LLR -8.82	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 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 17 kb · p 0.00027 · regional, not allelic
Overall
CADD	24.3	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.Pro727Ser
Coding: c.2179C>T
MANE Select: NM_001040142
dbSNP: rs1339703326
Type: single nucleotide variant
Location: chr2:165331359 (GRCh38)
Gene constraint: LOEUF 0.161 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 69.28 · 5 PDB
Residue 727: 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)

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

Similar variants

SCN2A p.Pro727Leu Uncertain significance ★ ⚠ same residue
SCN2A p.Ala1773Thr Pathogenic ★★★ same type
SCN2A p.Arg220Gly Likely pathogenic ★★★ same type
SCN2A p.Arg853Gln Pathogenic ★★★ same type
SCN2A p.Gly899Asp Likely pathogenic ★★★ same type
SCN2A p.Leu1611Pro Pathogenic ★★★ same type
SCN2A p.Leu886Ser Likely pathogenic ★★★ same type
SCN2A p.Lys1260Gln Likely pathogenic ★★★ same type

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-pro727ser (accessed [today's date]).

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