Is CERS1 p.Phe196Ile (c.586T>A) pathogenic?

CERS1 p.Phe196Ile (c.586T>A) is classified Uncertain significance in CERS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-18). AlphaMissense: likely pathogenic (0.9437); Very rare (popmax 0.00401%, afr); Associated with progressive myoclonic epilepsy type 8.

What condition is associated with CERS1 p.Phe196Ile (c.586T>A)?

CERS1 p.Phe196Ile (c.586T>A) is associated with progressive myoclonic epilepsy type 8 (ClinVar).

How common is CERS1 p.Phe196Ile (c.586T>A) in the general population?

CERS1 p.Phe196Ile (c.586T>A) is very rare (popmax 0.00401%, afr) (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.Phe196Ile (c.586T>A)?

AlphaMissense predicts likely pathogenic (score 0.9437) — an in-silico prediction, not a clinical call.

CERS1 p.Phe196Ile

c.586T>A · rs1184304135 · VCV2115426

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9437 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

progressive myoclonic epilepsy type 8

Computational evidence

Protein change
AlphaMissense	0.9437	likely pathogenic
REVEL	0.783	moderately pathogenic-leaning
SaProt	LLR -4.18	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.9	GERP 1.2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 25 kb · p 1 · regional, not allelic
Overall
CADD	25.5	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 0.00401% African / African-American · 3/74,876 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,611,822 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: CERS1
Protein: p.Phe196Ile
Coding: c.586T>A
MANE Select: NM_021267
dbSNP: rs1184304135
Type: single nucleotide variant
Location: chr19:18884091 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 88.95
Residue 196: 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

GDF1 p.Ala196Gly Uncertain significance ★ ⚠ same residue
GDF1 p.Ala196Thr 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-phe196ile (accessed [today's date]).

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