Is KL p.Ala203Ser (c.607G>T) pathogenic?

KL p.Ala203Ser (c.607G>T) is classified Benign/Likely benign in KL (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-23). AlphaMissense: likely benign (0.0836); Low-frequency (popmax 2.14%, afr); Associated with tumoral calcinosis, hyperphosphatemic, familial, 3.

What condition is associated with KL p.Ala203Ser (c.607G>T)?

KL p.Ala203Ser (c.607G>T) is associated with tumoral calcinosis, hyperphosphatemic, familial, 3 (ClinVar).

How common is KL p.Ala203Ser (c.607G>T) in the general population?

KL p.Ala203Ser (c.607G>T) is low-frequency (popmax 2.14%, afr) (gnomAD).

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.Ala203Ser (c.607G>T)?

AlphaMissense predicts likely benign (score 0.0836) — an in-silico prediction, not a clinical call.

KL p.Ala203Ser

c.607G>T · rs116289670 · VCV710027

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0836 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.14%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

tumoral calcinosis, hyperphosphatemic, familial, 3

Computational evidence

Protein change
AlphaMissense	0.0836	likely benign
REVEL	0.041	moderately benign-leaning
SaProt	LLR -5.97	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 -0.035	GERP -2.5
Regional constraint	o/e 0.97	unconstrained · MANE · 48 kb · p 0.22 · regional, not allelic
Overall
CADD	13.08	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 2.14% African / African-American · 1,602/74,982 alleles

Filtering AF 2.05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.01%

Overall 0.119% 1,897/1,600,704 alleles · low-frequency exomes 993/1,448,350 · genomes 904/152,354 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.14%	47
Remaining individualsnot grpmax-eligible	0.18%	554
Admixed American	0.148%	675
Middle Eastern	0.132%	756
European (non-Finnish)	0.00713%	14,018
South Asian	0.00332%	30,141

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.Ala203Ser
Coding: c.607G>T
MANE Select: NM_004795
dbSNP: rs116289670
Type: single nucleotide variant
Location: chr13:33017047 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.48 · 6 PDB
Residue 203: an α-helix; 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.Ala203Val 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-ala203ser (accessed [today's date]).

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