Is KRT83 p.Pro27fs (c.78dup) pathogenic?

KRT83 p.Pro27fs (c.78dup) is classified Likely pathogenic in KRT83 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). Ultra-rare (popmax 0.0637%, sas); Associated with erythrokeratodermia variabilis et progressiva 5.

What condition is associated with KRT83 p.Pro27fs (c.78dup)?

KRT83 p.Pro27fs (c.78dup) is associated with erythrokeratodermia variabilis et progressiva 5 (ClinVar).

How common is KRT83 p.Pro27fs (c.78dup) in the general population?

KRT83 p.Pro27fs (c.78dup) is ultra-rare (popmax 0.0637%, sas) (gnomAD).

How is Erythrokeratodermia variabilis inherited?

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

KRT83 p.Pro27fs

c.78dup · VCV4850579

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0637%, sas)

Conditions

erythrokeratodermia variabilis et progressiva 5

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 1 of 9
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.8	GERP 1.9, phastCons 0.98
Overall
CADD	27.4	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 0.0637% South Asian · 58/91,088 alleles

Filtering AF 0.0505% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0458%

Overall 0.00545% 88/1,613,412 alleles · ultra-rare exomes 78/1,461,056 · genomes 10/152,356 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0637%	1,570
Middle Eastern	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.0096%	10,415
European (non-Finnish)	0.0017%	58,997
Admixed American	0.00167%	60,034
African / African-American	0.00133%	75,066

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: KRT83
Protein: p.Pro27fs
Coding: c.78dup
MANE Select: NM_002282
Type: Duplication
Location: chr12:52321257 (GRCh38)
Gene constraint: LOEUF 1.226 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.81
Residue 27: the 'head' region

Full KRT83 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

erythrokeratodermia variabilis et progressiva 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Erythrokeratodermia variabilis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

KRT83 p.Pro27= Likely benign ★ same residue
KRT83 p.Thr454Met Uncertain significance ★★ ⚠ same condition
KRT83 p.Ile254Val Benign/Likely benign ★★ same condition
KRT83 p.Cys389Ter Uncertain significance ★ same condition
KRT83 p.Pro25fs Conflicting classifications of pathogenicity ★ same condition
KRT83 p.Ser271fs Conflicting classifications of pathogenicity ★ 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/krt83-p-pro27fs (accessed [today's date]).

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