Is CERS3 p.Arg75Ter (c.223C>T) pathogenic?

CERS3 p.Arg75Ter (c.223C>T) is classified Likely pathogenic in CERS3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-20). Very rare (popmax 0.00168%, amr); Associated with Abnormality of the skin.

What condition is associated with CERS3 p.Arg75Ter (c.223C>T)?

CERS3 p.Arg75Ter (c.223C>T) is associated with Abnormality of the skin, autosomal recessive congenital ichthyosis 9 (ClinVar).

How common is CERS3 p.Arg75Ter (c.223C>T) in the general population?

CERS3 p.Arg75Ter (c.223C>T) is very rare (popmax 0.00168%, amr) (gnomAD).

CERS3 p.Arg75Ter

c.223C>T · rs747911784 · VCV1180727

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00168%, amr)

Conditions

Abnormality of the skin

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 12
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP 0.39, phastCons 0.082
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00168% Admixed American · 1/59,500 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000274% 4/1,458,980 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00168%	59,500
South Asian	0.0011%	90,520
European (non-Finnish)	0.00017%	589,411

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.Arg75Ter
Coding: c.223C>T
MANE Select: NM_001378789
dbSNP: rs747911784
Type: single nucleotide variant
Location: chr15:100490882 (GRCh38)
Gene constraint: LOEUF 1.14 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.52
Residue 75: the 'homeobox-like' region

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

Disease context

Abnormality of the skin — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive congenital ichthyosis 9

Similar variants

CERS3 c.466-1G>T 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 p.Arg53= 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-arg75ter (accessed [today's date]).

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