Is KRT1 p.Ser21= (c.63T>A) pathogenic?

KRT1 p.Ser21= (c.63T>A) is classified Likely benign in KRT1 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-03-27). Ultra-rare (popmax 0.0243%, nfe).

How common is KRT1 p.Ser21= (c.63T>A) in the general population?

KRT1 p.Ser21= (c.63T>A) is ultra-rare (popmax 0.0243%, nfe) (gnomAD).

KRT1 p.Ser21=

c.63T>A · rs142164771 · VCV733357

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0243%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.43	GERP -3.1
Overall
CADD	5.912	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0243% European (non-Finnish) · 287/1,180,032 alleles

Filtering AF 0.022% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0211%

Overall 0.0198% 319/1,614,104 alleles · ultra-rare exomes 298/1,461,888 · genomes 21/152,216 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0336%	2,976
European (non-Finnish)grpmax	0.0243%	4,112
African / African-American	0.0107%	9,367
Admixed American	0.005%	20,004

Remaining individuals 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: KRT1
Protein: p.Ser21=
Coding: c.63T>A
MANE Select: NM_006121
dbSNP: rs142164771
Type: single nucleotide variant
Location: chr12:52680286 (GRCh38)
Gene constraint: LOEUF 0.7 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.62 · 3 PDB
Residue 21: a modified residue (phosphoserine); the 'head' region

Full KRT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KRT1 c.1255-1G>T Pathogenic ★★ same type
KRT1 c.591+1G>C Pathogenic ★★ same type
KRT1 p.Asn188Lys Pathogenic ★★ same type
KRT1 p.Asn188Ser Pathogenic/Likely pathogenic ★★ same type
KRT1 p.Ile195Asn Pathogenic/Likely pathogenic ★★ same type
KRT1 p.Ile479Thr Pathogenic/Likely pathogenic ★★ same type
KRT1 p.Leu187Phe Pathogenic ★★ same type
KRT1 p.Leu485Phe Pathogenic/Likely pathogenic ★★ 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/krt1-p-ser21 (accessed [today's date]).

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