Is CERS1 p.Pro279Thr (c.835C>A) pathogenic?

CERS1 p.Pro279Thr (c.835C>A) is classified Uncertain significance in CERS1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-10). AlphaMissense: likely pathogenic (0.8094); Very rare (popmax 0.000593%, nfe); Associated with progressive myoclonic epilepsy type 8.

What condition is associated with CERS1 p.Pro279Thr (c.835C>A)?

CERS1 p.Pro279Thr (c.835C>A) is associated with progressive myoclonic epilepsy type 8 (ClinVar).

How common is CERS1 p.Pro279Thr (c.835C>A) in the general population?

CERS1 p.Pro279Thr (c.835C>A) is very rare (popmax 0.000593%, nfe) (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.Pro279Thr (c.835C>A)?

AlphaMissense predicts likely pathogenic (score 0.8094) — an in-silico prediction, not a clinical call.

CERS1 p.Pro279Thr

c.835C>A · rs368072339 · VCV1445214

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8094 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

progressive myoclonic epilepsy type 8

Computational evidence

Protein change
AlphaMissense	0.8094	likely pathogenic
REVEL	0.794	moderately pathogenic-leaning
SaProt	LLR -10.72	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 9.7	GERP -0.28, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 25 kb · p 1 · regional, not allelic
Overall
CADD	28.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000593% European (non-Finnish) · 7/1,179,484 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.00236% 38/1,612,698 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0778%	1,285
Remaining individualsnot grpmax-eligible	0.0128%	7,804
European (non-Finnish)grpmax	0.000593%	168,498

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro279Thr
Coding: c.835C>A
MANE Select: NM_021267
dbSNP: rs368072339
Type: single nucleotide variant
Location: chr19:18879306 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 88.95
Residue 279: 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.Pro279Ala Uncertain significance ★ ⚠ same residue
CERS1 p.Pro279Arg 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
CERS1 p.Ala45Pro 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-pro279thr (accessed [today's date]).

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