Is CERS1 p.Arg228His (c.683G>A) pathogenic?

CERS1 p.Arg228His (c.683G>A) is classified Uncertain significance in CERS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-04). AlphaMissense: likely benign (0.1926); Rare (popmax 0.259%, eas); Associated with progressive myoclonic epilepsy type 8.

What condition is associated with CERS1 p.Arg228His (c.683G>A)?

CERS1 p.Arg228His (c.683G>A) is associated with progressive myoclonic epilepsy type 8 (ClinVar).

How common is CERS1 p.Arg228His (c.683G>A) in the general population?

CERS1 p.Arg228His (c.683G>A) is rare (popmax 0.259%, eas) (gnomAD).

How is Progressive myoclonic epilepsy type 8 inherited?

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

What do computational predictors say about CERS1 p.Arg228His (c.683G>A)?

AlphaMissense predicts likely benign (score 0.1926) — an in-silico prediction, not a clinical call.

CERS1 p.Arg228His

c.683G>A · rs777656031 · VCV943122

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1926 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.259%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

progressive myoclonic epilepsy type 8

Computational evidence

Protein change
AlphaMissense	0.1926	likely benign
REVEL	0.547	indeterminate
SaProt	LLR -7.82	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 3.3	GERP -0.15, phastCons 0.67
Regional constraint	o/e 1.00	unconstrained · MANE · 25 kb · p 1 · regional, not allelic
Overall
CADD	25.3	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

Grpmax group 0.259% East Asian · 108/41,720 alleles

Filtering AF 0.219% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.204%

Overall 0.00705% 110/1,559,496 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.259%	386
Admixed American	0.00194%	51,644
European (non-Finnish)	8.68e-05%	1,151,930

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: CERS1
Protein: p.Arg228His
Coding: c.683G>A
MANE Select: NM_021267
dbSNP: rs777656031
Type: single nucleotide variant
Location: chr19:18880343 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 88.95
Residue 228: a UniProt-annotated variant site (in epm8); the tlc domain

Full CERS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

progressive myoclonic epilepsy type 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Progressive myoclonic epilepsy type 8 (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood

Similar variants

CERS1 p.Arg228Cys Uncertain significance ★★ ⚠ same residue
CERS1 p.Arg228= Likely benign ★ same residue
GDF1 p.Ala228Thr Uncertain significance ★ ⚠ same residue
CERS1 p.Ala117Ser Uncertain significance ★★ ⚠ same condition
CERS1 p.Ala165Thr Uncertain significance ★★ ⚠ same condition
CERS1 p.Ala266Val Uncertain significance ★★ ⚠ same condition
CERS1 p.Ala286Val Uncertain significance ★★ ⚠ same condition
CERS1 p.Ala304Val 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/cers1-p-arg228his (accessed [today's date]).

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