Is KRT1 p.Ser186Pro (c.556T>C) pathogenic?

KRT1 p.Ser186Pro (c.556T>C) is classified Pathogenic in KRT1 (ClinVar, Single submitter, 2 submitters; last evaluated 2020-07-31). AlphaMissense: likely pathogenic (0.9773); Absent from gnomAD v4.1; Associated with KRT1-related disorder.

What condition is associated with KRT1 p.Ser186Pro (c.556T>C)?

KRT1 p.Ser186Pro (c.556T>C) is associated with KRT1-related disorder (ClinVar).

How common is KRT1 p.Ser186Pro (c.556T>C) in the general population?

KRT1 p.Ser186Pro (c.556T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about KRT1 p.Ser186Pro (c.556T>C)?

AlphaMissense predicts likely pathogenic (score 0.9773) — an in-silico prediction, not a clinical call.

KRT1 p.Ser186Pro

c.556T>C · rs60022878 · VCV66647

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9773 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

KRT1-related disorder

Computational evidence

Protein change
AlphaMissense	0.9773	likely pathogenic ✓ concordant with ClinVar · top 8% in KRT1
REVEL	0.606	indeterminate
SaProt	LLR -11.33	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -9	GERP -3.7
Regional constraint	o/e 0.96	unconstrained · MANE · 5,152 bp · p 0.25 · regional, not allelic
Overall
CADD	9.478	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: KRT1
Protein: p.Ser186Pro
Coding: c.556T>C
MANE Select: NM_006121
dbSNP: rs60022878
Type: single nucleotide variant
Location: chr12:52679793 (GRCh38)
Gene constraint: LOEUF 0.7 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.62 · 3 PDB
Residue 186: the if rod domain; a UniProt-annotated variant site (in palmoplantar keratoderma; and mild ichthyosis largely limited to the flexural areas); a UniProt-annotated variant site (in ehk1); the 'coil 1a' region

Full KRT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

KRT1-related disorder

Similar variants

KRT1 p.Asn188Lys Pathogenic ★★ same condition
KRT1 p.Ile195Asn Pathogenic/Likely pathogenic ★★ same condition
KRT1 p.Ser233Leu Pathogenic/Likely pathogenic ★★ ⚠ same condition
KRT1 c.1255-1G>C Pathogenic ★ same condition
KRT1 c.591+1G>A Pathogenic ★ same condition
KRT1 p.Met339Thr Likely pathogenic ★ same condition
KRT1 p.Leu162Pro Conflicting classifications of pathogenicity ★ ⚠ same condition
KRT1 p.Leu475Pro 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/krt1-p-ser186pro (accessed [today's date]).

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