Is KEL p.Thr421= (c.1263G>A) pathogenic?

KEL p.Thr421= (c.1263G>A) is classified Likely benign in KEL (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-03-12). Rare (popmax 0.117%, afr); Associated with KEL-related disorder.

What condition is associated with KEL p.Thr421= (c.1263G>A)?

KEL p.Thr421= (c.1263G>A) is associated with KEL-related disorder (ClinVar).

How common is KEL p.Thr421= (c.1263G>A) in the general population?

KEL p.Thr421= (c.1263G>A) is rare (popmax 0.117%, afr) (gnomAD).

KEL p.Thr421=

c.1263G>A · rs140212054 · VCV3058178

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.117%, afr)

Conditions

KEL-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -4.3	GERP -12
Overall
CADD	0.247	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.117% African / African-American · 88/75,050 alleles

Filtering AF 0.0975% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0901%

Overall 0.00861% 139/1,614,140 alleles · rare exomes 90/1,461,860 · genomes 49/152,280 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.117%	853
Admixed American	0.015%	6,669
Remaining individualsnot grpmax-eligible	0.0112%	8,930
East Asian	0.0111%	8,974
European (non-Finnish)	0.00237%	42,143
South Asian	0.0022%	45,536

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: KEL
Protein: p.Thr421=
Coding: c.1263G>A
MANE Select: NM_000420
dbSNP: rs140212054
Type: single nucleotide variant
Location: chr7:142946258 (GRCh38)
Gene constraint: LOEUF 1.11 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.46
Residue 421: the peptidase m13 domain

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

Disease context

KEL-related disorder

Similar variants

KEL p.Thr421Met Uncertain significance ★ ⚠ same residue
KEL p.Ala311Asp Uncertain significance ★ ⚠ same condition
KEL c.223+1G>C Pathogenic same condition
KEL c.1593-4A>T Benign same condition
KEL c.1703+5G>A Likely benign same condition
KEL c.736-10C>T Likely benign same condition
KEL p.Glu494Val Likely benign same condition
KEL p.Leu633= Benign 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/kel-p-thr421 (accessed [today's date]).

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