Is KL p.Arg171Ser (c.511C>A) pathogenic?

KL p.Arg171Ser (c.511C>A) is classified Conflicting classifications of pathogenicity in KL (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-01). AlphaMissense: likely benign (0.1461); Rare (popmax 0.239%, eas); Associated with tumoral calcinosis, hyperphosphatemic, familial, 3.

What condition is associated with KL p.Arg171Ser (c.511C>A)?

KL p.Arg171Ser (c.511C>A) is associated with tumoral calcinosis, hyperphosphatemic, familial, 3 (ClinVar).

How common is KL p.Arg171Ser (c.511C>A) in the general population?

KL p.Arg171Ser (c.511C>A) is rare (popmax 0.239%, eas) (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.Arg171Ser (c.511C>A)?

AlphaMissense predicts likely benign (score 0.1461) — an in-silico prediction, not a clinical call.

KL p.Arg171Ser

c.511C>A · rs200517420 · VCV311684

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1461 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.239%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

tumoral calcinosis, hyperphosphatemic, familial, 3

Computational evidence

Protein change
AlphaMissense	0.1461	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -8.55	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 5.8	GERP 0.97, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 48 kb · p 0.22 · regional, not allelic
Overall
CADD	21.9	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 0.239% East Asian · 107/44,696 alleles

Filtering AF 0.203% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.189%

Overall 0.00773% 124/1,604,860 alleles · rare exomes 105/1,452,504 · genomes 19/152,356 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.239%	418
Remaining individualsnot grpmax-eligible	0.0145%	6,904
South Asian	0.00222%	45,145
Admixed American	0.00169%	59,328
African / African-American	0.00133%	74,962
European (non-Finnish)	0.00034%	294,313

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.Arg171Ser
Coding: c.511C>A
MANE Select: NM_004795
dbSNP: rs200517420
Type: single nucleotide variant
Location: chr13:33016951 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.48 · 6 PDB
Residue 171: 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.Arg171Cys 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-arg171ser (accessed [today's date]).

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