Is KL p.Phe718Cys (c.2153T>G) pathogenic?

KL p.Phe718Cys (c.2153T>G) is classified Uncertain significance in KL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-01). AlphaMissense: likely pathogenic (0.7044); Very rare (popmax 0.000254%, nfe).

How common is KL p.Phe718Cys (c.2153T>G) in the general population?

KL p.Phe718Cys (c.2153T>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about KL p.Phe718Cys (c.2153T>G)?

AlphaMissense predicts likely pathogenic (score 0.7044) — an in-silico prediction, not a clinical call.

KL p.Phe718Cys

c.2153T>G · rs888110462 · VCV2806093

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7044 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7044	likely pathogenic
REVEL	0.566	indeterminate
SaProt	LLR -12.97	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 6	GERP 0.68, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 48 kb · p 0.22 · regional, not allelic
Overall
CADD	24.0	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 0.000254% European (non-Finnish) · 3/1,180,050 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,122 alleles · very rare exomes 2/1,461,892 · genomes 1/152,230 · joint denominator

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.Phe718Cys
Coding: c.2153T>G
MANE Select: NM_004795
dbSNP: rs888110462
Type: single nucleotide variant
Location: chr13:33061232 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.48 · 6 PDB
Residue 718: an α-helix; the 'glycosyl hydrolase-1 2' region

Full KL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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KL p.Ala663Thr Uncertain significance ★★ ⚠ same type
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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-phe718cys (accessed [today's date]).

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