Is CSTA p.Arg58Ter (c.172C>T) pathogenic?

CSTA p.Arg58Ter (c.172C>T) is classified Likely pathogenic in CSTA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-13). Ultra-rare (popmax 0.0317%, amr); Associated with peeling skin syndrome 4.

What condition is associated with CSTA p.Arg58Ter (c.172C>T)?

CSTA p.Arg58Ter (c.172C>T) is associated with peeling skin syndrome 4 (ClinVar).

How common is CSTA p.Arg58Ter (c.172C>T) in the general population?

CSTA p.Arg58Ter (c.172C>T) is ultra-rare (popmax 0.0317%, amr) (gnomAD).

How is Exfoliative ichthyosis inherited?

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

CSTA p.Arg58Ter

c.172C>T · rs149474339 · VCV208473

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0317%, amr)

Conditions

peeling skin syndrome 4

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	escapes	premature termination codon in the last exon (3 of 3) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.2	GERP -0.89
Overall
CADD	32.0	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 0.0317% Admixed American · 19/59,968 alleles

Filtering AF 0.0207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0172%

Overall 0.00285% 46/1,613,596 alleles · ultra-rare exomes 39/1,461,540 · genomes 7/152,056 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0317%	3,156
African / African-American	0.00401%	24,957
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600
European (non-Finnish)	0.00186%	53,625
South Asian	0.0011%	91,080

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: CSTA
Protein: p.Arg58Ter
Coding: c.172C>T
MANE Select: NM_005213
dbSNP: rs149474339
Type: single nucleotide variant
Location: chr3:122341442 (GRCh38)
Gene constraint: LOEUF 1.219 · pLI 0.12 (gnomAD)
Structure: AlphaFold pLDDT 93.57 · 14 PDB
Residue 58: a β-strand

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

Disease context

peeling skin syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Exfoliative ichthyosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

CSTA p.Arg58Gln Uncertain significance ★ ⚠ same residue
CSTA p.Arg58Pro Uncertain significance ★ ⚠ same residue
CSTA p.Lys22Ter Pathogenic ★★ same condition
CSTA c.67-2A>T Pathogenic ★ same condition
CSTA p.Tyr35Ter Likely pathogenic ★ same condition
CSTA p.Gln86Ter Pathogenic same condition
CSTA c.169-12A>C Benign ★★ same type
CSTA p.Lys91Asn 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/csta-p-arg58ter (accessed [today's date]).

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