Is SCN2A p.Ser565Phe (c.1694C>T) pathogenic?

SCN2A p.Ser565Phe (c.1694C>T) is classified Uncertain significance in SCN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-28). AlphaMissense: likely benign (0.3176); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with SCN2A p.Ser565Phe (c.1694C>T)?

SCN2A p.Ser565Phe (c.1694C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SCN2A p.Ser565Phe (c.1694C>T) in the general population?

SCN2A p.Ser565Phe (c.1694C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SCN2A p.Ser565Phe (c.1694C>T)?

AlphaMissense predicts likely benign (score 0.3176) — an in-silico prediction, not a clinical call.

SCN2A p.Ser565Phe

c.1694C>T · VCV4160597

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3176 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3176	likely benign
REVEL	0.707	pathogenic-leaning
SaProt	LLR -10.18	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 17 kb · p 0.00027 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

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.Ser565Phe
Coding: c.1694C>T
MANE Select: NM_001040142
Type: single nucleotide variant
Location: chr2:165323178 (GRCh38)
Gene constraint: LOEUF 0.161 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 69.28 · 5 PDB
Residue 565: 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)

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

Similar variants

SCN2A p.Ser565= Likely benign ★ same residue
SCN2A c.386+2T>C Pathogenic ★★ same condition
SCN2A p.Arg1235Ter Pathogenic ★★ same condition
SCN2A p.Arg1629His Pathogenic/Likely pathogenic ★★ same condition
SCN2A p.Gln268Ter Pathogenic ★★ same condition
SCN2A p.Gln510Ter Pathogenic ★★ same condition
SCN2A p.Gln786Ter Pathogenic ★★ same condition
SCN2A p.Gly266Arg 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-ser565phe (accessed [today's date]).

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