Is KRT2 p.Arg45Cys (c.133C>T) pathogenic?

KRT2 p.Arg45Cys (c.133C>T) is classified Benign/Likely benign in KRT2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-17). AlphaMissense: ambiguous (0.3929); Rare (popmax 0.276%, eas); Associated with superficial epidermolytic ichthyosis.

What condition is associated with KRT2 p.Arg45Cys (c.133C>T)?

KRT2 p.Arg45Cys (c.133C>T) is associated with superficial epidermolytic ichthyosis (ClinVar).

How common is KRT2 p.Arg45Cys (c.133C>T) in the general population?

KRT2 p.Arg45Cys (c.133C>T) is rare (popmax 0.276%, eas) (gnomAD).

How is Superficial epidermolytic ichthyosis inherited?

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

What do computational predictors say about KRT2 p.Arg45Cys (c.133C>T)?

AlphaMissense predicts ambiguous (score 0.3929) — an in-silico prediction, not a clinical call.

KRT2 p.Arg45Cys

c.133C>T · rs202186833 · VCV309628

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3929 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.276%, eas)

Conditions

superficial epidermolytic ichthyosis

Computational evidence

Protein change
AlphaMissense	0.3929	ambiguous
REVEL	0.56	indeterminate
SaProt	LLR -8.65	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.8	GERP -1.2, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 7,120 bp · p 0.023 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.276% East Asian · 124/44,884 alleles

Filtering AF 0.237% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.222%

Overall 0.0115% 186/1,610,804 alleles · rare exomes 170/1,458,560 · genomes 16/152,244 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.276%	362
Ashkenazi Jewishnot grpmax-eligible	0.0203%	4,933
South Asian	0.00879%	11,381
Remaining individualsnot grpmax-eligible	0.008%	12,496
European (non-Finnish)	0.00356%	28,092
African / African-American	0.00133%	75,024

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.Arg45Cys
Coding: c.133C>T
MANE Select: NM_000423
dbSNP: rs202186833
Type: single nucleotide variant
Location: chr12:52652010 (GRCh38)
Gene constraint: LOEUF 1 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.38
Residue 45: the 'head' 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.Arg45His Likely benign ★★ same residue
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

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-arg45cys (accessed [today's date]).

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