Is SGCE p.His422Pro (c.1265A>C) pathogenic?

SGCE p.His422Pro (c.1265A>C) is classified Uncertain significance in SGCE (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-28). AlphaMissense: likely benign (0.0819); Very rare (popmax 0.00195%, nfe); Associated with myoclonic dystonia 11.

What condition is associated with SGCE p.His422Pro (c.1265A>C)?

SGCE p.His422Pro (c.1265A>C) is associated with myoclonic dystonia 11 (ClinVar).

How common is SGCE p.His422Pro (c.1265A>C) in the general population?

SGCE p.His422Pro (c.1265A>C) is very rare (popmax 0.00195%, nfe) (gnomAD).

How is Myoclonus-dystonia syndrome inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about SGCE p.His422Pro (c.1265A>C)?

AlphaMissense predicts likely benign (score 0.0819) — an in-silico prediction, not a clinical call.

SGCE p.His422Pro

c.1265A>C · rs1208271707 · VCV2722148

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0819 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00195%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

myoclonic dystonia 11

Computational evidence

Protein change
AlphaMissense	0.0819	likely benign
REVEL	0.493	indeterminate
SaProt	LLR -4.81	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 5.1	GERP 1.6, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 71 kb · p 0.00058 · regional, not allelic
Overall
CADD	22.2	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

Grpmax group 0.00195% European (non-Finnish) · 23/1,178,356 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00109%

Overall 0.00143% 23/1,612,120 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: SGCE
Protein: p.His422Pro
Coding: c.1265A>C
MANE Select: NM_022900 · reported on NM_003919
dbSNP: rs1208271707
Type: single nucleotide variant
Location: chr7:94588721 (GRCh38)

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

Disease context

myoclonic dystonia 11 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Myoclonus-dystonia syndrome (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 1 000 000 (Europe)

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/sgce-p-his422pro (accessed [today's date]).

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