Is KRT1 p.Arg463= (c.1389C>T) pathogenic?

KRT1 p.Arg463= (c.1389C>T) is classified Benign in KRT1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-02). Common (popmax 47.3%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with diffuse nonepidermolytic palmoplantar keratoderma.

KRT1 p.Arg463=

Q: What condition is associated with KRT1 p.Arg463= (c.1389C>T)?

KRT1 p.Arg463= (c.1389C>T) is associated with diffuse nonepidermolytic palmoplantar keratoderma, epidermolytic ichthyosis (ClinVar).

Q: How common is KRT1 p.Arg463= (c.1389C>T) in the general population?

KRT1 p.Arg463= (c.1389C>T) is common (popmax 47.3%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is KRT1-related diffuse nonepidermolytic keratoderma inherited?

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

c.1389C>T · rs936958 · VCV66623

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 47.3%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

diffuse nonepidermolytic palmoplantar keratoderma

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 -20	GERP -4.3
Overall
CADD	0.076	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 47.3% European (non-Finnish) · 557,532/1,179,492 alleles

Filtering AF 47.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 47.1%

Overall 46.1% 743,031/1,613,358 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	73.5%	1
Ashkenazi Jewishnot grpmax-eligible	47.8%	2
European (non-Finnish)grpmax	47.3%	2
African / African-American	47.1%	2
Finnishnot grpmax-eligible	47%	2
South Asian	45.3%	2
Remaining individualsnot grpmax-eligible	45.1%	2
Middle Eastern	41.6%	2
Admixed American	39.4%	3
East Asian	21.7%	5

Amish 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: KRT1
Protein: p.Arg463=
Coding: c.1389C>T
MANE Select: NM_006121
dbSNP: rs936958
Type: single nucleotide variant
Location: chr12:52676361 (GRCh38)
Gene constraint: LOEUF 0.7 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.62 · 3 PDB
Residue 463: the if rod domain; a UniProt-annotated variant site (in palmoplantar keratoderma; and mild ichthyosis largely limited to the flexural areas); an α-helix; the 'coil 2' region

Full KRT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

diffuse nonepidermolytic palmoplantar keratoderma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: epidermolytic ichthyosis

For KRT1-related diffuse nonepidermolytic keratoderma (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood, Infancy

Similar variants

KRT1 c.1255-1G>T Pathogenic ★★ same condition
KRT1 p.Asn188Lys Pathogenic ★★ same condition
KRT1 p.Leu485Phe Pathogenic/Likely pathogenic ★★ same condition
KRT1 p.Arg86His Uncertain significance ★★ ⚠ same condition
KRT1 p.Gly556Ser Uncertain significance ★★ ⚠ same condition
KRT1 c.1511-11T>C Benign/Likely benign ★★ same condition
KRT1 c.592-8G>A Benign/Likely benign ★★ same condition
KRT1 c.*344C>T 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/krt1-p-arg463 (accessed [today's date]).

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