Is KL p.Ala749= (c.2247T>C) pathogenic?

KL p.Ala749= (c.2247T>C) is classified Benign in KL (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). Common (popmax 85.6%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with tumoral calcinosis, hyperphosphatemic, familial, 3.

What condition is associated with KL p.Ala749= (c.2247T>C)?

KL p.Ala749= (c.2247T>C) is associated with tumoral calcinosis, hyperphosphatemic, familial, 3 (ClinVar).

How is Familial tumoral calcinosis inherited?

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

KL p.Ala749=

Q: How common is KL p.Ala749= (c.2247T>C) in the general population?

KL p.Ala749= (c.2247T>C) is common (popmax 85.6%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2247T>C · rs648202 · VCV311701

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 85.6%, nfe) — too common for a highly-penetrant pathogenic allele

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 -14	GERP -3.8
Overall
CADD	0.159	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 85.6% European (non-Finnish) · 1,009,965/1,180,012 alleles

Filtering AF 85.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 85.4%

Overall 83.3% 1,343,674/1,613,948 alleles · common exomes 1,226,991/1,461,868 · genomes 116,683/152,080 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	91%	1
Finnishnot grpmax-eligible	88.2%	1
Amishnot grpmax-eligible	87.4%	1
European (non-Finnish)grpmax	85.6%	1
Middle Eastern	84%	1
Remaining individualsnot grpmax-eligible	82.3%	1
South Asian	81.3%	1
Admixed American	79.6%	1
East Asian	62.6%	2
African / African-American	57.6%	2

Ashkenazi Jewish 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: KL
Protein: p.Ala749=
Coding: c.2247T>C
MANE Select: NM_004795
dbSNP: rs648202
Type: single nucleotide variant
Location: chr13:33061326 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.48 · 6 PDB
Residue 749: an α-helix; the 'glycosyl hydrolase-1 2' 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.Ala749Ser 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-ala749 (accessed [today's date]).

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