Is KRT2 p.Thr500= (c.1500T>C) pathogenic?

KRT2 p.Thr500= (c.1500T>C) is classified Benign in KRT2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-14). Rare (popmax 0.496%, afr); Associated with superficial epidermolytic ichthyosis.

What condition is associated with KRT2 p.Thr500= (c.1500T>C)?

KRT2 p.Thr500= (c.1500T>C) is associated with superficial epidermolytic ichthyosis (ClinVar).

How common is KRT2 p.Thr500= (c.1500T>C) in the general population?

KRT2 p.Thr500= (c.1500T>C) is rare (popmax 0.496%, afr) (gnomAD).

How is Superficial epidermolytic ichthyosis inherited?

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

KRT2 p.Thr500=

c.1500T>C · rs142620105 · VCV309600

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.496%, afr)

Conditions

superficial epidermolytic ichthyosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.74 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.12	GERP -1.2
Overall
CADD	2.63	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.496% African / African-American · 372/75,056 alleles

Filtering AF 0.454% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.438%

Overall 0.027% 436/1,614,198 alleles · rare exomes 241/1,461,870 · genomes 195/152,328 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.496%	202
Middle Eastern	0.066%	1,516
Remaining individualsnot grpmax-eligible	0.0416%	2,404
Admixed American	0.0367%	2,728
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
South Asian	0.0011%	91,074
European (non-Finnish)	0.000847%	118,002

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: KRT2
Protein: p.Thr500=
Coding: c.1500T>C
MANE Select: NM_000423
dbSNP: rs142620105
Type: single nucleotide variant
Location: chr12:52645539 (GRCh38)
Gene constraint: LOEUF 1 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.38
Residue 500: the 'tail' region

Full KRT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

superficial epidermolytic ichthyosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Superficial epidermolytic ichthyosis (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal

Similar variants

KRT2 p.Glu487Lys Pathogenic ★★ same condition
KRT2 p.Glu488Lys Likely pathogenic ★★ same condition
KRT2 c.1249-4A>G Benign ★★ same condition
KRT2 c.1249-7G>T Benign ★★ same condition
KRT2 c.861+6C>G Benign/Likely benign ★★ same condition
KRT2 c.*215C>T Benign ★★ same condition
KRT2 c.*42T>C Benign ★★ same condition
KRT2 p.Ala427= 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/krt2-p-thr500 (accessed [today's date]).

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