Is CERS3 p.Arg229Cys (c.685C>T) pathogenic?

CERS3 p.Arg229Cys (c.685C>T) is classified Pathogenic in CERS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-11). AlphaMissense: likely pathogenic (0.7158); Very rare (popmax 0.0022%, sas); Associated with lamellar ichthyosis.

What condition is associated with CERS3 p.Arg229Cys (c.685C>T)?

CERS3 p.Arg229Cys (c.685C>T) is associated with lamellar ichthyosis (ClinVar).

How common is CERS3 p.Arg229Cys (c.685C>T) in the general population?

CERS3 p.Arg229Cys (c.685C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

How is Lamellar ichthyosis inherited?

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

What do computational predictors say about CERS3 p.Arg229Cys (c.685C>T)?

AlphaMissense predicts likely pathogenic (score 0.7158) — an in-silico prediction, not a clinical call.

CERS3 p.Arg229Cys

c.685C>T · VCV3384753

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7158 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

lamellar ichthyosis

Computational evidence

Protein change
AlphaMissense	0.7158	likely pathogenic ✓ concordant with ClinVar
REVEL	0.862	moderately pathogenic-leaning
SaProt	LLR -15.11	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 99 kb · p 0.65 · regional, not allelic
Overall
CADD	34.0	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 0.0022% South Asian · 2/91,064 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000372% 6/1,613,690 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,532
Admixed American	0.00167%	59,988
African / African-American	0.00134%	74,894
European (non-Finnish)	0.00017%	589,904

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.Arg229Cys
Coding: c.685C>T
MANE Select: NM_001378789
Type: single nucleotide variant
Location: chr15:100472977 (GRCh38)
Gene constraint: LOEUF 1.14 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.52
Residue 229: the tlc domain

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

Disease context

lamellar ichthyosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Lamellar ichthyosis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

CERS3 p.Arg229His Pathogenic ★ same residue
CERS3 p.Arg229Ser Uncertain significance ★ ⚠ same residue
CERS3 c.466-1G>T Likely pathogenic ★★ same type
CERS3 p.Arg75Ter Likely pathogenic ★★ same type
CERS3 p.Arg275Cys Uncertain significance ★★ ⚠ same type
CERS3 p.Ser177Phe Uncertain significance ★★ ⚠ same type
CERS3 c.174-81G>A Benign ★★ same type
CERS3 c.407+74C>T Benign ★★ same type

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-arg229cys (accessed [today's date]).

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