Is KRT2 p.Arg45His (c.134G>A) pathogenic?

KRT2 p.Arg45His (c.134G>A) is classified Likely benign in KRT2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-06-13). AlphaMissense: likely benign (0.3005); Low-frequency (popmax 1.65%, mid); Associated with superficial epidermolytic ichthyosis.

What condition is associated with KRT2 p.Arg45His (c.134G>A)?

KRT2 p.Arg45His (c.134G>A) is associated with superficial epidermolytic ichthyosis (ClinVar).

How common is KRT2 p.Arg45His (c.134G>A) in the general population?

KRT2 p.Arg45His (c.134G>A) is low-frequency (popmax 1.65%, mid) (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.Arg45His (c.134G>A)?

AlphaMissense predicts likely benign (score 0.3005) — an in-silico prediction, not a clinical call.

KRT2 p.Arg45His

c.134G>A · rs149447253 · VCV309627

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.3005 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.65%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

superficial epidermolytic ichthyosis

Computational evidence

Protein change
AlphaMissense	0.3005	likely benign
REVEL	0.291	indeterminate
SaProt	LLR -8.48	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 0.06, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 7,120 bp · p 0.023 · regional, not allelic
Overall
CADD	23.4	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 1.65% Middle Eastern · 100/6,060 alleles

Filtering AF 1.39% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.29%

Overall 0.022% 354/1,611,142 alleles · low-frequency exomes 318/1,458,830 · genomes 36/152,312 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	1.65%	61
Remaining individualsnot grpmax-eligible	0.0656%	1,524
Admixed American	0.0566%	1,766
East Asian	0.0401%	2,494
South Asian	0.0395%	2,530
African / African-American	0.02%	5,003
European (non-Finnish)	0.00907%	11,027
Finnishnot grpmax-eligible	0.0049%	20,396

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.Arg45His
Coding: c.134G>A
MANE Select: NM_000423
dbSNP: rs149447253
Type: single nucleotide variant
Location: chr12:52652009 (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.Arg45Cys Benign/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-arg45his (accessed [today's date]).

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