Is KRT83 p.Cys389Ter (c.1167C>A) pathogenic?

KRT83 p.Cys389Ter (c.1167C>A) is classified Uncertain significance in KRT83 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-19). Ultra-rare (popmax 0.0184%, mid); Associated with monilethrix-1.

What condition is associated with KRT83 p.Cys389Ter (c.1167C>A)?

KRT83 p.Cys389Ter (c.1167C>A) is associated with monilethrix-1, erythrokeratodermia variabilis et progressiva 5 (ClinVar).

How common is KRT83 p.Cys389Ter (c.1167C>A) in the general population?

KRT83 p.Cys389Ter (c.1167C>A) is ultra-rare (popmax 0.0184%, mid) (gnomAD).

How is Monilethrix inherited?

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

KRT83 p.Cys389Ter

c.1167C>A · VCV3891538

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0184%, mid)

Conditions

monilethrix-1

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 7 of 9
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP 1.9
Overall
CADD	44.0	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 0.0184% Middle Eastern · 1/5,422 alleles

Filtering AF 0.00639% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00592%

Overall 0.0062% 100/1,613,124 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0184%	5,422
Remaining individualsnot grpmax-eligible	0.00961%	10,401
European (non-Finnish)	0.00771%	12,966
African / African-American	0.00267%	37,440

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.Cys389Ter
Coding: c.1167C>A
MANE Select: NM_002282
Type: single nucleotide variant
Location: chr12:52315988 (GRCh38)
Gene constraint: LOEUF 1.226 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.81
Residue 389: the if rod domain; the 'coil 2' region

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

Disease context

monilethrix-1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: erythrokeratodermia variabilis et progressiva 5

For Monilethrix (Orphanet):

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

Similar variants

KRT83 p.Cys389= Likely benign ★ same residue
KRT83 p.Thr454Met Uncertain significance ★★ ⚠ same condition
KRT83 p.Ile254Val Benign/Likely benign ★★ same condition
KRT83 p.Pro27fs Likely pathogenic ★ same condition
KRT83 p.Pro25fs Conflicting classifications of pathogenicity ★ same condition
KRT83 p.Ser271fs Conflicting classifications of pathogenicity ★ same condition
KRT83 p.Glu407Lys Likely pathogenic ★★ same type
KRT83 p.Arg130Cys Uncertain significance ★★ ⚠ 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/krt83-p-cys389ter (accessed [today's date]).

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