Is KL p.Ser319Phe (c.956C>T) pathogenic?

KL p.Ser319Phe (c.956C>T) is classified Uncertain significance in KL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-24). AlphaMissense: likely pathogenic (0.9321); Ultra-rare (popmax 0.0221%, nfe); Associated with tumoral calcinosis, hyperphosphatemic, familial, 3.

What condition is associated with KL p.Ser319Phe (c.956C>T)?

KL p.Ser319Phe (c.956C>T) is associated with tumoral calcinosis, hyperphosphatemic, familial, 3 (ClinVar).

How common is KL p.Ser319Phe (c.956C>T) in the general population?

KL p.Ser319Phe (c.956C>T) is ultra-rare (popmax 0.0221%, nfe) (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.Ser319Phe (c.956C>T)?

AlphaMissense predicts likely pathogenic (score 0.9321) — an in-silico prediction, not a clinical call.

KL p.Ser319Phe

c.956C>T · rs138955761 · VCV311688

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9321 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0221%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

tumoral calcinosis, hyperphosphatemic, familial, 3

Computational evidence

Protein change
AlphaMissense	0.9321	likely pathogenic · top 5% in KL
REVEL	0.429	indeterminate
SaProt	LLR -13.01	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 48 kb · p 0.22 · regional, not allelic
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0221% European (non-Finnish) · 261/1,180,026 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.019%

Overall 0.0166% 268/1,614,036 alleles · ultra-rare exomes 256/1,461,888 · genomes 12/152,148 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0221%	4,521
Remaining individualsnot grpmax-eligible	0.0096%	10,415
African / African-American	0.00133%	74,912

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.Ser319Phe
Coding: c.956C>T
MANE Select: NM_004795
dbSNP: rs138955761
Type: single nucleotide variant
Location: chr13:33053903 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.48 · 6 PDB
Residue 319: 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

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KL p.Arg594Cys Uncertain significance ★★ ⚠ same condition
KL p.Arg620Cys Uncertain significance ★★ ⚠ same condition
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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-ser319phe (accessed [today's date]).

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