Is CERS1 p.Ala86Val (c.257C>T) pathogenic?

CERS1 p.Ala86Val (c.257C>T) is classified Uncertain significance in CERS1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-11-15). AlphaMissense: likely pathogenic (0.6588); Ultra-rare (popmax 0.0392%, nfe); Associated with progressive myoclonic epilepsy type 8.

What condition is associated with CERS1 p.Ala86Val (c.257C>T)?

CERS1 p.Ala86Val (c.257C>T) is associated with progressive myoclonic epilepsy type 8 (ClinVar).

How common is CERS1 p.Ala86Val (c.257C>T) in the general population?

CERS1 p.Ala86Val (c.257C>T) is ultra-rare (popmax 0.0392%, 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.Ala86Val (c.257C>T)?

AlphaMissense predicts likely pathogenic (score 0.6588) — an in-silico prediction, not a clinical call.

CERS1 p.Ala86Val

c.257C>T · rs374895377 · VCV542127

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6588 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0392%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

progressive myoclonic epilepsy type 8

Computational evidence

Protein change
AlphaMissense	0.6588	likely pathogenic
REVEL	0.158	moderately benign-leaning
SaProt	LLR -11.59	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP 0.48, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 25 kb · p 1 · regional, not allelic
Overall
CADD	22.9	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 0.0392% European (non-Finnish) · 462/1,177,920 alleles

Filtering AF 0.0363% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0351%

Overall 0.0315% 507/1,607,730 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0392%	2,550
Remaining individualsnot grpmax-eligible	0.0289%	3,457
African / African-American	0.0147%	6,803
South Asian	0.0133%	7,494
Finnishnot grpmax-eligible	0.0048%	20,847
East Asian	0.00224%	44,698

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.Ala86Val
Coding: c.257C>T
MANE Select: NM_021267
dbSNP: rs374895377
Type: single nucleotide variant
Location: chr19:18893568 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 88.95
Residue 86: a UniProt-annotated variant site (in epm8)

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.Ala86= Likely benign ★ 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
CERS1 p.Ala97Thr 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-ala86val (accessed [today's date]).

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