Is KL p.Ala249= (c.747C>T) pathogenic?

KL p.Ala249= (c.747C>T) is classified Conflicting classifications of pathogenicity in KL (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-30). Rare (popmax 0.671%, eas); Associated with tumoral calcinosis, hyperphosphatemic, familial, 3.

What condition is associated with KL p.Ala249= (c.747C>T)?

KL p.Ala249= (c.747C>T) is associated with tumoral calcinosis, hyperphosphatemic, familial, 3 (ClinVar).

How common is KL p.Ala249= (c.747C>T) in the general population?

KL p.Ala249= (c.747C>T) is rare (popmax 0.671%, eas) (gnomAD).

How is Familial tumoral calcinosis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

KL p.Ala249=

c.747C>T · rs563017227 · VCV883761

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.671%, eas)

Conditions

tumoral calcinosis, hyperphosphatemic, familial, 3

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 3.2	GERP -0.1, phastCons 1
Overall
CADD	14.6	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.671% East Asian · 301/44,834 alleles

Filtering AF 0.609% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.585%

Overall 0.0195% 312/1,598,522 alleles · rare exomes 295/1,446,154 · genomes 17/152,368 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.671%	149
Remaining individualsnot grpmax-eligible	0.016%	6,234
Admixed American	0.00167%	59,900

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: KL
Protein: p.Ala249=
Coding: c.747C>T
MANE Select: NM_004795
dbSNP: rs563017227
Type: single nucleotide variant
Location: chr13:33017187 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.48 · 6 PDB
Residue 249: a β-strand; the 'glycosyl hydrolase-1 1' region

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

Disease context

tumoral calcinosis, hyperphosphatemic, familial, 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial tumoral calcinosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

KL p.Ala249Thr Uncertain significance ★ ⚠ same residue
KL c.1331-3C>A Uncertain significance ★★ same condition
KL p.Ala987Thr Uncertain significance ★★ ⚠ same condition
KL p.Arg179Trp Uncertain significance ★★ ⚠ same condition
KL p.Arg594Cys Uncertain significance ★★ ⚠ same condition
KL p.Arg620Cys Uncertain significance ★★ ⚠ same condition
KL p.Arg628Cys Uncertain significance ★★ ⚠ same condition
KL p.Arg751Gly 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/kl-p-ala249 (accessed [today's date]).

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