Is SCN3A p.Ser528Pro (c.1582T>C) pathogenic?

SCN3A p.Ser528Pro (c.1582T>C) is classified Uncertain significance in SCN3A (ClinVar, Single submitter, 1 submitter; last evaluated 2026-03-03). AlphaMissense: ambiguous (0.5497); Very rare (popmax 0.0011%, sas); Associated with Inborn genetic diseases.

What condition is associated with SCN3A p.Ser528Pro (c.1582T>C)?

SCN3A p.Ser528Pro (c.1582T>C) is associated with Inborn genetic diseases (ClinVar).

How common is SCN3A p.Ser528Pro (c.1582T>C) in the general population?

SCN3A p.Ser528Pro (c.1582T>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about SCN3A p.Ser528Pro (c.1582T>C)?

AlphaMissense predicts ambiguous (score 0.5497) — an in-silico prediction, not a clinical call.

SCN3A p.Ser528Pro

c.1582T>C · VCV4840922

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5497 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5497	ambiguous
REVEL	0.76	pathogenic-leaning
SaProt	LLR -7.21	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.9, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 23 kb · p 4.6e-06 · regional, not allelic
Overall
CADD	24.9	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

Grpmax group 0.0011% South Asian · 1/91,078 alleles

Overall 6.84e-05% 1/1,461,810 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: SCN3A
Protein: p.Ser528Pro
Coding: c.1582T>C
MANE Select: NM_006922
Type: single nucleotide variant
Location: chr2:165146828 (GRCh38)
Gene constraint: LOEUF 0.348 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.76 · 2 PDB
Residue 528: the 'disordered' region

Full SCN3A 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

SCN3A p.Ser528Ala Uncertain significance ★ ⚠ same residue
SCN3A p.Ser528= Likely benign ★ same residue
SCN3A p.Phe1646Ser Likely pathogenic ★★ same condition
SCN3A p.Val1769Ala Likely pathogenic ★★ same condition
SCN3A c.694+5G>C Uncertain significance ★★ same condition
SCN3A p.Ala1512Glu Uncertain significance ★★ ⚠ same condition
SCN3A p.Ala1905Thr Uncertain significance ★★ ⚠ same condition
SCN3A p.Ala34Gly Uncertain significance ★★ ⚠ 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/scn3a-p-ser528pro (accessed [today's date]).

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