Is KRT2 p.Cys42Phe (c.125G>T) pathogenic?

KRT2 p.Cys42Phe (c.125G>T) is classified Uncertain significance in KRT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-02). AlphaMissense: ambiguous (0.3821); No allele count reported in gnomAD v4.1 (AN 1,610,122); Associated with Inborn genetic diseases.

What condition is associated with KRT2 p.Cys42Phe (c.125G>T)?

KRT2 p.Cys42Phe (c.125G>T) is associated with Inborn genetic diseases (ClinVar).

How common is KRT2 p.Cys42Phe (c.125G>T) in the general population?

KRT2 p.Cys42Phe (c.125G>T) is no allele count reported in gnomAD v4.1 (AN 1,610,122) (gnomAD).

What do computational predictors say about KRT2 p.Cys42Phe (c.125G>T)?

AlphaMissense predicts ambiguous (score 0.3821) — an in-silico prediction, not a clinical call.

KRT2 p.Cys42Phe

c.125G>T · VCV3865423

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3821 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,610,122)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3821	ambiguous
REVEL	0.28	benign-leaning
SaProt	LLR -7.29	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.1	GERP 2, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 7,120 bp · p 0.023 · regional, not allelic
Overall
CADD	23.6	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

No allele count reported in gnomAD v4.1 (AN 1,610,122). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: KRT2
Protein: p.Cys42Phe
Coding: c.125G>T
MANE Select: NM_000423
Type: single nucleotide variant
Location: chr12:52652018 (GRCh38)
Gene constraint: LOEUF 1 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.38
Residue 42: the 'head' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KRT2 p.Arg544Gln Uncertain significance ★★ ⚠ same condition
KRT2 p.Asn498Ile Uncertain significance ★★ ⚠ same condition
KRT2 p.Val402Met Likely benign ★★ same condition
KRT2 p.Ala190Ser Uncertain significance ★ ⚠ same condition
KRT2 p.Ala278Thr Uncertain significance ★ ⚠ same condition
KRT2 p.Ala350Thr Uncertain significance ★ ⚠ same condition
KRT2 p.Ala369Ser Uncertain significance ★ ⚠ same condition
KRT2 p.Ala369Val Uncertain significance ★ ⚠ 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-cys42phe (accessed [today's date]).

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