Is KL p.Pro514Ser (c.1540C>T) pathogenic?

KL p.Pro514Ser (c.1540C>T) is classified Benign/Likely benign in KL (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.1294); Common (popmax 10.5%, amr) — too common for a highly-penetrant pathogenic allele; Associated with tumoral calcinosis, hyperphosphatemic, familial, 3.

What condition is associated with KL p.Pro514Ser (c.1540C>T)?

KL p.Pro514Ser (c.1540C>T) 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.

What do computational predictors say about KL p.Pro514Ser (c.1540C>T)?

AlphaMissense predicts likely benign (score 0.1294) — an in-silico prediction, not a clinical call.

KL p.Pro514Ser

Q: How common is KL p.Pro514Ser (c.1540C>T) in the general population?

KL p.Pro514Ser (c.1540C>T) is common (popmax 10.5%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1540C>T · rs3752472 · VCV311695

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1294 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 10.5%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

tumoral calcinosis, hyperphosphatemic, familial, 3

Computational evidence

Protein change
AlphaMissense	0.1294	likely benign
REVEL	0.186	benign-leaning
SaProt	LLR -8.90	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 48 kb · p 0.22 · regional, not allelic
Overall
CADD	20.4	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 10.5% Admixed American · 6,282/60,008 alleles

Filtering AF 10.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 10.2%

Overall 0.93% 15,010/1,614,160 alleles · common exomes 12,584/1,461,866 · genomes 2,426/152,294 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	10.5%	10
East Asian	8.44%	12
South Asian	1.51%	66
African / African-American	1.42%	71
Remaining individualsnot grpmax-eligible	1.21%	82
Finnishnot grpmax-eligible	1.08%	93
Ashkenazi Jewishnot grpmax-eligible	0.966%	104
Middle Eastern	0.313%	319
European (non-Finnish)	0.0635%	1,575

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.Pro514Ser
Coding: c.1540C>T
MANE Select: NM_004795
dbSNP: rs3752472
Type: single nucleotide variant
Location: chr13:33055256 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.48 · 6 PDB
Residue 514: a UniProt-annotated variant site (in); an α-helix

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 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
KL p.Arg853Cys 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-pro514ser (accessed [today's date]).

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