Is SCN8A p.Ser845Pro (c.2533T>C) pathogenic?

SCN8A p.Ser845Pro (c.2533T>C) is classified Likely pathogenic in SCN8A (ClinVar, Expert panel, 2 submitters; last evaluated 2025-08-26). AlphaMissense: likely pathogenic (0.975); Absent from gnomAD v4.1; Associated with complex neurodevelopmental disorder.

What condition is associated with SCN8A p.Ser845Pro (c.2533T>C)?

SCN8A p.Ser845Pro (c.2533T>C) is associated with complex neurodevelopmental disorder (ClinVar).

How common is SCN8A p.Ser845Pro (c.2533T>C) in the general population?

SCN8A p.Ser845Pro (c.2533T>C) is absent from gnomAD v4.1 (gnomAD).

How is Non-specific syndromic intellectual disability inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about SCN8A p.Ser845Pro (c.2533T>C)?

AlphaMissense predicts likely pathogenic (score 0.975) — an in-silico prediction, not a clinical call.

SCN8A p.Ser845Pro

c.2533T>C · rs1057518356 · VCV373333

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.975 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

complex neurodevelopmental disorder

ClinGen expert panel — Epilepsy Sodium Channel VCEP

Likely Pathogenic for complex neurodevelopmental disorder. Applied ACMG criteria (verbatim):

PP3_Moderate PM2_Supporting PM5_Supporting PM1

Curation rationale (ClinGen, verbatim)

The NM_001330260.2:c.2533T>C variant in SCN8A is a missense variant predicted to cause substitution of serine by proline at amino acid 845 (p.Ser845Pro). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.960, which is above the threshold of 0.773, evidence that correlates with impact to SCN8A function (PP3_Moderate). Another missense variant (c.2534C>T (p.Ser845Phe), ClinVar Variation ID: 207109) in the same codon has been classified as likely pathogenic for autosomal dominant complex neurodevelopmental disorder by the ClinGen Epilepsy Sodium Channel VCEP (PM5_Supporting). This variant resides within a region, amino acids 844-852, of SCN8A that is defined as a mutational hotspot and/or critical functional domain by the ClinGen Epilepsy Sodium Channel VCEP (PM1). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PM1, PP3_Moderate, PM2_Supporting, PM5_Supporting. (VCEP specifications version 2.0.0; approved 8/26/25).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.975	likely pathogenic ✓ concordant with ClinVar
REVEL	0.96	strongly pathogenic-leaning
SaProt	LLR -10.41	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 7.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.21	constrained · MANE · 17 kb · p 8.5e-44 · regional, not allelic
Overall
CADD	27.0	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: SCN8A
Protein: p.Ser845Pro
Coding: c.2533T>C
MANE Select: NM_001330260
dbSNP: rs1057518356
Type: single nucleotide variant
Location: chr12:51762665 (GRCh38)
Gene constraint: LOEUF 0.189 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.90 · 7 PDB

Full SCN8A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

complex neurodevelopmental disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Non-specific syndromic intellectual disability (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Childhood, Infancy

Similar variants

SCN8A p.Ser845Cys Likely pathogenic ★★★ ⚠ same residue
SCN8A p.Ser845Phe Likely pathogenic ★★★ ⚠ same residue
SCN8A c.615-1G>A Pathogenic ★★★ same condition
SCN8A p.Arg1872Gln Pathogenic ★★★ ⚠ same condition
SCN8A p.Asn1318Ser Likely pathogenic ★★★ same condition
SCN8A p.Asn418Asp Likely pathogenic ★★★ same condition
SCN8A p.Glu1218Lys Pathogenic ★★★ same condition
SCN8A p.Ile1631Thr 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/scn8a-p-ser845pro (accessed [today's date]).

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