Is CERS3 p.Ile99Ser (c.296T>G) pathogenic?

CERS3 p.Ile99Ser (c.296T>G) is classified Uncertain significance in CERS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-23). AlphaMissense: likely benign (0.3314); Ultra-rare (popmax 0.0379%, eas); Associated with Inborn genetic diseases.

What condition is associated with CERS3 p.Ile99Ser (c.296T>G)?

CERS3 p.Ile99Ser (c.296T>G) is associated with Inborn genetic diseases (ClinVar).

How common is CERS3 p.Ile99Ser (c.296T>G) in the general population?

CERS3 p.Ile99Ser (c.296T>G) is ultra-rare (popmax 0.0379%, eas) (gnomAD).

What do computational predictors say about CERS3 p.Ile99Ser (c.296T>G)?

AlphaMissense predicts likely benign (score 0.3314) — an in-silico prediction, not a clinical call.

CERS3 p.Ile99Ser

c.296T>G · VCV3266327

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3314 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0379%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3314	likely benign
REVEL	0.868	moderately pathogenic-leaning
SaProt	LLR -13.28	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 99 kb · p 0.65 · regional, not allelic
Overall
CADD	27.6	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 0.0379% East Asian · 17/44,872 alleles

Filtering AF 0.0241% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.00105% 17/1,611,514 alleles · ultra-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: CERS3
Protein: p.Ile99Ser
Coding: c.296T>G
MANE Select: NM_001378789
Type: single nucleotide variant
Location: chr15:100484661 (GRCh38)
Gene constraint: LOEUF 1.14 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.52
Residue 99: the 'homeobox-like' region

Full CERS3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CERS3 p.Arg275Cys Uncertain significance ★★ ⚠ same condition
CERS3 p.Ser177Phe Uncertain significance ★★ ⚠ same condition
CERS3 p.Val60Ile Likely benign ★★ same condition
CERS3 p.Ala151Val Uncertain significance ★ ⚠ same condition
CERS3 p.Arg111Gly Uncertain significance ★ ⚠ same condition
CERS3 p.Arg128Met Uncertain significance ★ ⚠ same condition
CERS3 p.Arg339Lys Uncertain significance ★ ⚠ same condition
CERS3 p.Arg54Cys 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/cers3-p-ile99ser (accessed [today's date]).

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