Is KRT5 p.Phe46Ile (c.136T>A) pathogenic?

KRT5 p.Phe46Ile (c.136T>A) is classified Conflicting classifications of pathogenicity in KRT5 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-23). AlphaMissense: likely benign (0.115); Ultra-rare (popmax 0.0483%, amr); Associated with Inborn genetic diseases.

What condition is associated with KRT5 p.Phe46Ile (c.136T>A)?

KRT5 p.Phe46Ile (c.136T>A) is associated with Inborn genetic diseases (ClinVar).

How common is KRT5 p.Phe46Ile (c.136T>A) in the general population?

KRT5 p.Phe46Ile (c.136T>A) is ultra-rare (popmax 0.0483%, amr) (gnomAD).

What do computational predictors say about KRT5 p.Phe46Ile (c.136T>A)?

AlphaMissense predicts likely benign (score 0.115) — an in-silico prediction, not a clinical call.

KRT5 p.Phe46Ile

c.136T>A · rs777631293 · VCV2885424

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.115 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0483%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.115	likely benign
REVEL	0.059	moderately benign-leaning
SaProt	LLR -7.21	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 1,321 bp · p 0.7 · regional, not allelic
Overall
CADD	14.81	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

Grpmax group 0.0483% Admixed American · 29/60,004 alleles

Filtering AF 0.0345% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0299%

Overall 0.0018% 29/1,613,788 alleles · ultra-rare exomes 27/1,461,618 · genomes 2/152,170 · joint denominator

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: KRT5
Protein: p.Phe46Ile
Coding: c.136T>A
MANE Select: NM_000424
dbSNP: rs777631293
Type: single nucleotide variant
Location: chr12:52520161 (GRCh38)
Gene constraint: LOEUF 0.538 · pLI 0.90 (gnomAD)
Structure: AlphaFold pLDDT 68.86 · 2 PDB
Residue 46: the 'head' region; a UniProt-annotated variant site (in ddd1)

Full KRT5 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

KRT5 p.Pro25Leu Pathogenic ★★ same condition
KRT5 p.Ala101Thr Uncertain significance ★★ ⚠ same condition
KRT5 p.Ala20Thr Uncertain significance ★★ ⚠ same condition
KRT5 p.Arg169His Uncertain significance ★★ ⚠ same condition
KRT5 p.Arg239Cys Uncertain significance ★★ ⚠ same condition
KRT5 p.Arg354Trp Uncertain significance ★★ ⚠ same condition
KRT5 p.Arg559Gln Uncertain significance ★★ ⚠ same condition
KRT5 p.Arg585Trp 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/krt5-p-phe46ile (accessed [today's date]).

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