Is KL p.Phe352Val (c.1054T>G) pathogenic?

KL p.Phe352Val (c.1054T>G) is classified Benign in KL (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-03). AlphaMissense: ambiguous (0.4881); Common (popmax 18.1%, afr) — too common for a highly-penetrant pathogenic allele; Associated with tumoral calcinosis, hyperphosphatemic, familial, 3.

What condition is associated with KL p.Phe352Val (c.1054T>G)?

KL p.Phe352Val (c.1054T>G) 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.Phe352Val (c.1054T>G)?

AlphaMissense predicts ambiguous (score 0.4881) — an in-silico prediction, not a clinical call.

KL p.Phe352Val

Q: How common is KL p.Phe352Val (c.1054T>G) in the general population?

KL p.Phe352Val (c.1054T>G) is common (popmax 18.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1054T>G · rs9536314 · VCV311690

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

ambiguous

0.4881 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 18.1%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

tumoral calcinosis, hyperphosphatemic, familial, 3

Computational evidence

Protein change
AlphaMissense	0.4881	ambiguous
REVEL	0.409	indeterminate
SaProt	LLR -12.28	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 48 kb · p 0.22 · regional, not allelic
Overall
CADD	26.6	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 18.1% African / African-American · 13,536/74,928 alleles

Filtering AF 17.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 17.7%

Overall 15.4% 248,912/1,612,748 alleles · common exomes 225,219/1,460,648 · genomes 23,693/152,100 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	20.9%	5
Finnishnot grpmax-eligible	19.7%	5
African / African-Americangrpmax	18.1%	6
South Asian	17.3%	6
Remaining individualsnot grpmax-eligible	16.4%	6
Middle Eastern	16.2%	6
European (non-Finnish)	15.6%	6
Amishnot grpmax-eligible	10.6%	9
Admixed American	8.35%	12
East Asian	0.0869%	1,150

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.Phe352Val
Coding: c.1054T>G
MANE Select: NM_004795
dbSNP: rs9536314
Type: single nucleotide variant
Location: chr13:33054001 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.48 · 6 PDB
Residue 352: a UniProt-annotated variant site (in allele kl-vs); the 'glycosyl hydrolase-1 1' region; 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-phe352val (accessed [today's date]).

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