Is KRT6A p.Phe174Val (c.520T>G) pathogenic?

KRT6A p.Phe174Val (c.520T>G) is classified Pathogenic in KRT6A (ClinVar, No assertion criteria, 2 submitters; last evaluated 2001-12-01). AlphaMissense: likely pathogenic (0.9925); No allele count reported in gnomAD v4.1 (AN 1,613,926); Associated with pachyonychia congenita 3.

What condition is associated with KRT6A p.Phe174Val (c.520T>G)?

KRT6A p.Phe174Val (c.520T>G) is associated with pachyonychia congenita 3 (ClinVar).

How common is KRT6A p.Phe174Val (c.520T>G) in the general population?

KRT6A p.Phe174Val (c.520T>G) is no allele count reported in gnomAD v4.1 (AN 1,613,926) (gnomAD).

How is Pachyonychia congenita inherited?

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

What do computational predictors say about KRT6A p.Phe174Val (c.520T>G)?

AlphaMissense predicts likely pathogenic (score 0.9925) — an in-silico prediction, not a clinical call.

KRT6A p.Phe174Val

c.520T>G · rs28933087 · VCV14635

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9925 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,613,926)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pachyonychia congenita 3

Computational evidence

Protein change
AlphaMissense	0.9925	likely pathogenic ✓ concordant with ClinVar · top 5% in KRT6A
REVEL	0.952	strongly pathogenic-leaning
SaProt	LLR -14.04	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 5,122 bp · p 0.98 · regional, not allelic
Overall
CADD	25.5	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 1,613,926). 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: KRT6A
Protein: p.Phe174Val
Coding: c.520T>G
MANE Select: NM_005554
dbSNP: rs28933087
Type: single nucleotide variant
Location: chr12:52492669 (GRCh38)
Gene constraint: LOEUF 0.755 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.16 · 1 PDB
Residue 174: the if rod domain; a UniProt-annotated variant site (in pc3); the 'coil 1a' region

Full KRT6A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

pachyonychia congenita 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Pachyonychia congenita (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages

Similar variants

KRT6A p.Phe174Ile Likely pathogenic ★ same residue
KRT6A p.Phe174Ser Pathogenic same residue
KRT6A c.1460-1G>C Pathogenic/Likely pathogenic ★★ same condition
KRT6A p.Asn171Lys Pathogenic ★★ same condition
KRT6A p.Asn171Ser Pathogenic ★★ same condition
KRT6A p.Glu163Lys Pathogenic ★★ same condition
KRT6A p.Glu472Lys Pathogenic/Likely pathogenic ★★ same condition
KRT6A p.Leu170Phe 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/krt6a-p-phe174val (accessed [today's date]).

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