Is CST6 p.Arg99fs (c.295del) pathogenic?

CST6 p.Arg99fs (c.295del) is classified Likely pathogenic in CST6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-30). Very rare (popmax 0.00167%, amr); Associated with ectodermal dysplasia 15, hypohidrotic/hair type.

What condition is associated with CST6 p.Arg99fs (c.295del)?

CST6 p.Arg99fs (c.295del) is associated with ectodermal dysplasia 15, hypohidrotic/hair type (ClinVar).

How common is CST6 p.Arg99fs (c.295del) in the general population?

CST6 p.Arg99fs (c.295del) is very rare (popmax 0.00167%, amr) (gnomAD).

CST6 p.Arg99fs

c.295del · VCV4845922

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

ectodermal dysplasia 15, hypohidrotic/hair type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 3
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,002 alleles

Overall 6.2e-05% 1/1,613,390 alleles · very rare exomes 1/1,461,182 · genomes 0/152,208 · joint denominator

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: CST6
Protein: p.Arg99fs
Coding: c.295del
MANE Select: NM_001323
Type: Deletion
Location: chr11:66012879 (GRCh38)
Gene constraint: LOEUF 1.488 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.46 · 5 PDB
Residue 99: a β-strand

Full CST6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ectodermal dysplasia 15, hypohidrotic/hair type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CST6 p.Arg99Cys Uncertain significance ★ ⚠ same residue
CST6 p.Ala21Val Uncertain significance ★ ⚠ same condition
CST6 p.Gln140Ter Uncertain significance ★ same condition
CST6 p.Gln121Ter 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/cst6-p-arg99fs (accessed [today's date]).

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