Is KRT5 p.Ser582Phe (c.1745C>T) pathogenic?

KRT5 p.Ser582Phe (c.1745C>T) is classified Uncertain significance in KRT5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-10). AlphaMissense: likely pathogenic (0.7449); Ultra-rare (popmax 0.0143%, sas); Associated with Inborn genetic diseases.

What condition is associated with KRT5 p.Ser582Phe (c.1745C>T)?

KRT5 p.Ser582Phe (c.1745C>T) is associated with Inborn genetic diseases (ClinVar).

How common is KRT5 p.Ser582Phe (c.1745C>T) in the general population?

KRT5 p.Ser582Phe (c.1745C>T) is ultra-rare (popmax 0.0143%, sas) (gnomAD).

What do computational predictors say about KRT5 p.Ser582Phe (c.1745C>T)?

AlphaMissense predicts likely pathogenic (score 0.7449) — an in-silico prediction, not a clinical call.

KRT5 p.Ser582Phe

c.1745C>T · VCV4045046

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7449 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0143%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7449	likely pathogenic
REVEL	0.411	indeterminate
SaProt	LLR -12.98	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 10	phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 2,753 bp · p 0.69 · regional, not allelic
Overall
CADD	27.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0143% South Asian · 13/91,038 alleles

Filtering AF 0.00845% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00661%

Overall 0.000868% 14/1,613,688 alleles · ultra-rare exomes 14/1,461,506 · genomes 0/152,182 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0143%	7,003
European (non-Finnish)	8.47e-05%	1,179,993

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.Ser582Phe
Coding: c.1745C>T
MANE Select: NM_000424
Type: single nucleotide variant
Location: chr12:52514970 (GRCh38)
Gene constraint: LOEUF 0.538 · pLI 0.90 (gnomAD)
Structure: AlphaFold pLDDT 68.86 · 2 PDB
Residue 582: the 'disordered' region; a UniProt-annotated variant site (found in a patient with ebs with an unspecified subtype; likely pathogenic); a UniProt-annotated variant site (in ddd1); the 'tail' region

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-ser582phe (accessed [today's date]).

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