Is KRT2 p.Arg34Gln (c.101G>A) pathogenic?

KRT2 p.Arg34Gln (c.101G>A) is classified Uncertain significance in KRT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-30). AlphaMissense: likely benign (0.1726); Ultra-rare (popmax 0.0624%, eas); Associated with superficial epidermolytic ichthyosis.

What condition is associated with KRT2 p.Arg34Gln (c.101G>A)?

KRT2 p.Arg34Gln (c.101G>A) is associated with superficial epidermolytic ichthyosis (ClinVar).

How common is KRT2 p.Arg34Gln (c.101G>A) in the general population?

KRT2 p.Arg34Gln (c.101G>A) is ultra-rare (popmax 0.0624%, 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.Arg34Gln (c.101G>A)?

AlphaMissense predicts likely benign (score 0.1726) — an in-silico prediction, not a clinical call.

KRT2 p.Arg34Gln

c.101G>A · VCV3891523

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1726 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0624%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

superficial epidermolytic ichthyosis

Computational evidence

Protein change
AlphaMissense	0.1726	likely benign
REVEL	0.341	indeterminate
SaProt	LLR -7.88	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 0.8	GERP 2.1, phastCons 0.53
Regional constraint	o/e 1.08	unconstrained · MANE · 7,120 bp · p 0.023 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0624% East Asian · 28/44,880 alleles

Filtering AF 0.0443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0382%

Overall 0.00679% 109/1,605,734 alleles · ultra-rare exomes 96/1,453,432 · genomes 13/152,302 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0624%	1,603
South Asian	0.0275%	3,641
Middle Eastern	0.0165%	6,058
Remaining individualsnot grpmax-eligible	0.016%	6,245
African / African-American	0.00666%	15,008
European (non-Finnish)	0.00339%	29,497

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.Arg34Gln
Coding: c.101G>A
MANE Select: NM_000423
Type: single nucleotide variant
Location: chr12:52652042 (GRCh38)
Gene constraint: LOEUF 1 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.38
Residue 34: 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.Arg34Trp 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-arg34gln (accessed [today's date]).

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