Is KRT5 p.Arg352Cys (c.1054C>T) pathogenic?

KRT5 p.Arg352Cys (c.1054C>T) is classified Uncertain significance in KRT5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-16). AlphaMissense: ambiguous (0.4371); Very rare (popmax 0.004%, afr); Associated with epidermolysis bullosa simplex 2E, with migratory circinate erythema.

What condition is associated with KRT5 p.Arg352Cys (c.1054C>T)?

KRT5 p.Arg352Cys (c.1054C>T) is associated with epidermolysis bullosa simplex 2E, with migratory circinate erythema, epidermolysis bullosa simplex 1A, generalized severe, epidermolysis bullosa simplex 2F, with mottled pigmentation (ClinVar).

How common is KRT5 p.Arg352Cys (c.1054C>T) in the general population?

KRT5 p.Arg352Cys (c.1054C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about KRT5 p.Arg352Cys (c.1054C>T)?

AlphaMissense predicts ambiguous (score 0.4371) — an in-silico prediction, not a clinical call.

KRT5 p.Arg352Cys

Q: How is Epidermolysis bullosa simplex with circinate migratory erythema inherited?

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

c.1054C>T · VCV3891528

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4371 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

epidermolysis bullosa simplex 2E, with migratory circinate erythema

Computational evidence

Protein change
AlphaMissense	0.4371	ambiguous
REVEL	0.8	moderately pathogenic-leaning
SaProt	LLR -12.87	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 2,753 bp · p 0.69 · regional, not allelic
Overall
CADD	34.0	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 0.004% African / African-American · 3/74,920 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00204% 33/1,614,042 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,973
Admixed American	0.00333%	30,006
European (non-Finnish)	0.00229%	43,705
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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: KRT5
Protein: p.Arg352Cys
Coding: c.1054C>T
MANE Select: NM_000424
Type: single nucleotide variant
Location: chr12:52517628 (GRCh38)
Gene constraint: LOEUF 0.538 · pLI 0.90 (gnomAD)
Structure: AlphaFold pLDDT 68.86 · 2 PDB
Residue 352: the if rod domain; a UniProt-annotated variant site (in ddd1); the 'coil 2' region; a UniProt-annotated variant site (in ebs2c)

Full KRT5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

epidermolysis bullosa simplex 2E, with migratory circinate erythema — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: epidermolysis bullosa simplex 1A, generalized severe epidermolysis bullosa simplex 2F, with mottled pigmentation Dowling-Degos disease 1 epidermolysis bullosa simplex 2A, generalized severe epidermolysis bullosa simplex 2B, generalized intermediate epidermolysis bullosa simplex 2C, localized epidermolysis bullosa simplex 2d, generalized, intermediate or severe, autosomal recessive

For Epidermolysis bullosa simplex with circinate migratory erythema (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal

Similar variants

KRT5 p.Arg352His Likely benign ★ ⚠ same residue
KRT5 c.555+1G>A Pathogenic ★★ same condition
KRT5 p.Arg331Cys Pathogenic/Likely pathogenic ★★ same condition
KRT5 p.Asn176Ser Pathogenic/Likely pathogenic ★★ same condition
KRT5 p.Glu170Lys Pathogenic ★★ same condition
KRT5 p.Glu477Lys Pathogenic ★★ same condition
KRT5 p.Gly476Asp Pathogenic/Likely pathogenic ★★ same condition
KRT5 p.Ile161Ser Pathogenic ★★ 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/krt5-p-arg352cys (accessed [today's date]).

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