Is CERS1 p.Arg228Cys (c.682C>T) pathogenic?

CERS1 p.Arg228Cys (c.682C>T) is classified Uncertain significance in CERS1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-07). AlphaMissense: likely benign (0.2726); Very rare (popmax 0.00591%, sas); Associated with progressive myoclonic epilepsy type 8.

What condition is associated with CERS1 p.Arg228Cys (c.682C>T)?

CERS1 p.Arg228Cys (c.682C>T) is associated with progressive myoclonic epilepsy type 8 (ClinVar).

How common is CERS1 p.Arg228Cys (c.682C>T) in the general population?

CERS1 p.Arg228Cys (c.682C>T) is very rare (popmax 0.00591%, sas) (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.Arg228Cys (c.682C>T)?

AlphaMissense predicts likely benign (score 0.2726) — an in-silico prediction, not a clinical call.

CERS1 p.Arg228Cys

c.682C>T · rs746909154 · VCV1374905

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2726 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00591%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

progressive myoclonic epilepsy type 8

Computational evidence

Protein change
AlphaMissense	0.2726	likely benign
REVEL	0.518	indeterminate
SaProt	LLR -9.33	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 1	GERP -2, phastCons 0.62
Regional constraint	o/e 1.00	unconstrained · MANE · 25 kb · p 1 · regional, not allelic
Overall
CADD	23.5	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 0.00591% South Asian · 5/84,638 alleles

Filtering AF 0.00233% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00145%

Overall 0.000923% 13/1,408,374 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00591%	16,928
Ashkenazi Jewishnot grpmax-eligible	0.00348%	28,758
Finnishnot grpmax-eligible	0.0033%	30,311
East Asian	0.00239%	41,760
Admixed American	0.00193%	51,788
Remaining individualsnot grpmax-eligible	0.00165%	60,502
European (non-Finnish)	0.000174%	576,286

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.Arg228Cys
Coding: c.682C>T
MANE Select: NM_021267
dbSNP: rs746909154
Type: single nucleotide variant
Location: chr19:18880344 (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.Arg228His 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-arg228cys (accessed [today's date]).

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