Is CERS3 p.Arg53= (c.159A>G) pathogenic?

CERS3 p.Arg53= (c.159A>G) is classified Benign in CERS3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Common (popmax 92.4%, eas) — too common for a highly-penetrant pathogenic allele; Associated with autosomal recessive congenital ichthyosis 9.

What condition is associated with CERS3 p.Arg53= (c.159A>G)?

CERS3 p.Arg53= (c.159A>G) is associated with autosomal recessive congenital ichthyosis 9 (ClinVar).

How is Congenital ichthyosiform erythroderma inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

CERS3 p.Arg53=

Q: How common is CERS3 p.Arg53= (c.159A>G) in the general population?

CERS3 p.Arg53= (c.159A>G) is common (popmax 92.4%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.159A>G · rs1354332 · VCV1209733

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 92.4%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

autosomal recessive congenital ichthyosis 9

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -0.63, phastCons 0.93
Overall
CADD	10.57	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 92.4% East Asian · 41,445/44,844 alleles

Filtering AF 91.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 91.4%

Overall 86.5% 1,394,362/1,612,716 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	92.4%	1
Amishnot grpmax-eligible	90.2%	1
European (non-Finnish)	88.6%	1
South Asian	86.7%	1
Ashkenazi Jewishnot grpmax-eligible	86.5%	1
Remaining individualsnot grpmax-eligible	85.5%	1
Finnishnot grpmax-eligible	85.1%	1
Middle Eastern	83.3%	1
Admixed American	80.4%	1
African / African-American	55.8%	2

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.Arg53=
Coding: c.159A>G
MANE Select: NM_001378789
dbSNP: rs1354332
Type: single nucleotide variant
Location: chr15:100501691 (GRCh38)
Gene constraint: LOEUF 1.14 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.52

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

Disease context

autosomal recessive congenital ichthyosis 9 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Congenital ichthyosiform erythroderma (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Spain)

Similar variants

CERS3 c.466-1G>T Likely pathogenic ★★ same condition
CERS3 p.Arg75Ter Likely pathogenic ★★ same condition
CERS3 p.Ser177Phe Uncertain significance ★★ ⚠ same condition
CERS3 c.845+53C>T Benign ★★ same condition
CERS3 c.999+60G>A Benign ★★ same condition
CERS3 c.*75C>A Benign ★★ same condition
CERS3 p.Arg370Gly Benign ★★ same condition
CERS3 c.609+1G>T Likely pathogenic ★ 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-arg53 (accessed [today's date]).

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