Is KRT83 p.Pro475= (c.1425C>T) pathogenic?

KRT83 p.Pro475= (c.1425C>T) is classified Uncertain significance in KRT83 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Very rare (popmax 0.000172%, nfe); Associated with monilethrix.

What condition is associated with KRT83 p.Pro475= (c.1425C>T)?

KRT83 p.Pro475= (c.1425C>T) is associated with monilethrix (ClinVar).

How common is KRT83 p.Pro475= (c.1425C>T) in the general population?

KRT83 p.Pro475= (c.1425C>T) is very rare (popmax 0.000172%, nfe) (gnomAD).

How is Monilethrix inherited?

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

KRT83 p.Pro475=

c.1425C>T · rs757638030 · VCV880641

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000172%, nfe)

Conditions

monilethrix

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 1.6, phastCons 1
Overall
CADD	1.999	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000172% European (non-Finnish) · 2/1,164,976 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.00158% 25/1,583,520 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0692%	1,446
Remaining individualsnot grpmax-eligible	0.00489%	20,431
European (non-Finnish)grpmax	0.000172%	582,489

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro475=
Coding: c.1425C>T
MANE Select: NM_002282
dbSNP: rs757638030
Type: single nucleotide variant
Location: chr12:52314688 (GRCh38)
Gene constraint: LOEUF 1.226 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.81
Residue 475: the 'tail' region

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

Disease context

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

For Monilethrix (Orphanet):

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

Similar variants

KRT83 p.Pro475Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
KRT83 p.Glu407Lys Likely pathogenic ★★ same condition
KRT83 p.Arg168Trp Uncertain significance ★★ ⚠ same condition
KRT83 p.Arg272Gln Uncertain significance ★★ ⚠ same condition
KRT83 p.Glu172Lys Uncertain significance ★★ ⚠ same condition
KRT83 c.1041+6A>G Benign ★★ same condition
KRT83 c.1042-4C>A Benign ★★ same condition
KRT83 c.750+15A>G Benign ★★ 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-pro475 (accessed [today's date]).

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