Is KRT5 p.Ser499Pro (c.1495T>C) pathogenic?

KRT5 p.Ser499Pro (c.1495T>C) is classified Likely benign in KRT5 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: likely benign (0.2719); Very rare (popmax 0.00246%, nfe); Associated with epidermolysis bullosa simplex.

What condition is associated with KRT5 p.Ser499Pro (c.1495T>C)?

KRT5 p.Ser499Pro (c.1495T>C) is associated with epidermolysis bullosa simplex (ClinVar).

How common is KRT5 p.Ser499Pro (c.1495T>C) in the general population?

KRT5 p.Ser499Pro (c.1495T>C) is very rare (popmax 0.00246%, nfe) (gnomAD).

What do computational predictors say about KRT5 p.Ser499Pro (c.1495T>C)?

AlphaMissense predicts likely benign (score 0.2719) — an in-silico prediction, not a clinical call.

KRT5 p.Ser499Pro

c.1495T>C · rs201274668 · VCV884124

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2719 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00246%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

epidermolysis bullosa simplex

Computational evidence

Protein change
AlphaMissense	0.2719	likely benign
REVEL	0.493	indeterminate
SaProt	LLR -8.42	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 2,753 bp · p 0.69 · regional, not allelic
Overall
CADD	21.6	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 0.00246% European (non-Finnish) · 29/1,179,974 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00696% 112/1,608,892 alleles · very rare exomes 101/1,456,814 · genomes 11/152,078 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.129%	776
Remaining individualsnot grpmax-eligible	0.0112%	8,924
European (non-Finnish)grpmax	0.00246%	40,689

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser499Pro
Coding: c.1495T>C
MANE Select: NM_000424
dbSNP: rs201274668
Type: single nucleotide variant
Location: chr12:52515220 (GRCh38)
Gene constraint: LOEUF 0.538 · pLI 0.90 (gnomAD)
Structure: AlphaFold pLDDT 68.86 · 2 PDB
Residue 499: 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

epidermolysis bullosa simplex — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KRT5 p.Ala428Thr Pathogenic/Likely pathogenic ★★ same condition
KRT5 p.Ala428Val Pathogenic/Likely pathogenic ★★ same condition
KRT5 p.Glu170Lys Pathogenic ★★ same condition
KRT5 p.Glu466Gln Pathogenic/Likely pathogenic ★★ same condition
KRT5 p.Glu477Lys Pathogenic ★★ same condition
KRT5 p.Leu196Pro Pathogenic/Likely pathogenic ★★ same condition
KRT5 p.Leu463Pro Pathogenic ★★ same condition
KRT5 p.Pro25Leu 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/krt5-p-ser499pro (accessed [today's date]).

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