Is KRT2 p.Phe189Ser (c.566T>C) pathogenic?

KRT2 p.Phe189Ser (c.566T>C) is classified Conflicting classifications of pathogenicity in KRT2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-11-12). AlphaMissense: likely pathogenic (0.9982); Absent from gnomAD v4.1; Associated with KRT2-related disorder.

What condition is associated with KRT2 p.Phe189Ser (c.566T>C)?

KRT2 p.Phe189Ser (c.566T>C) is associated with KRT2-related disorder (ClinVar).

How common is KRT2 p.Phe189Ser (c.566T>C) in the general population?

KRT2 p.Phe189Ser (c.566T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about KRT2 p.Phe189Ser (c.566T>C)?

AlphaMissense predicts likely pathogenic (score 0.9982) — an in-silico prediction, not a clinical call.

KRT2 p.Phe189Ser

c.566T>C · rs1064795317 · VCV421717

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9982 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

KRT2-related disorder

Computational evidence

Protein change
AlphaMissense	0.9982	likely pathogenic · top 1% in KRT2
REVEL	0.958	strongly pathogenic-leaning
SaProt	LLR -14.61	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.1	GERP 2.1, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 7,120 bp · p 0.023 · regional, not allelic
Overall
CADD	31.0	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

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: KRT2
Protein: p.Phe189Ser
Coding: c.566T>C
MANE Select: NM_000423
dbSNP: rs1064795317
Type: single nucleotide variant
Location: chr12:52651577 (GRCh38)
Gene constraint: LOEUF 1 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.38
Residue 189: the if rod domain; the 'coil 1a' region

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

Disease context

KRT2-related disorder

Similar variants

KRT2 p.Glu487Lys Pathogenic ★★ same condition
KRT2 p.Thr479Pro Likely pathogenic ★ same condition
KRT2 p.Ala425Gly Likely benign ⚠ same condition
KRT2 p.Leu406= Likely benign same condition
KRT2 p.Glu488Lys Likely pathogenic ★★ same type
KRT2 p.Arg544Gln Uncertain significance ★★ ⚠ same type
KRT2 p.Asn498Ile Uncertain significance ★★ ⚠ same type
KRT2 c.1122+16G>A Benign ★★ same type

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-phe189ser (accessed [today's date]).

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