Is KL p.Ala50Val (c.149C>T) pathogenic?

KL p.Ala50Val (c.149C>T) is classified Uncertain significance in KL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-24). AlphaMissense: likely benign (0.0869); Ultra-rare (popmax 0.0127%, eas).

How common is KL p.Ala50Val (c.149C>T) in the general population?

KL p.Ala50Val (c.149C>T) is ultra-rare (popmax 0.0127%, eas) (gnomAD).

What do computational predictors say about KL p.Ala50Val (c.149C>T)?

AlphaMissense predicts likely benign (score 0.0869) — an in-silico prediction, not a clinical call.

KL p.Ala50Val

c.149C>T · rs1186993804 · VCV1447707

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0869 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0127%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0869	likely benign
REVEL	0.016	strongly benign-leaning
SaProt	LLR -5.49	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 -0.044	GERP -2.4
Regional constraint	o/e 0.97	unconstrained · MANE · 48 kb · p 0.22 · regional, not allelic
Overall
CADD	7.972	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0127% East Asian · 5/39,348 alleles

Filtering AF 0.00494% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00319%

Overall 0.0018% 27/1,496,688 alleles · ultra-rare exomes 24/1,344,958 · genomes 3/151,730 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0127%	7,870
European (non-Finnish)	0.00187%	53,516
Finnishnot grpmax-eligible	0.00182%	54,890

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.Ala50Val
Coding: c.149C>T
MANE Select: NM_004795
dbSNP: rs1186993804
Type: single nucleotide variant
Location: chr13:33016589 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.48 · 6 PDB
Residue 50: an α-helix

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

Similar variants

KL c.1331-3C>A Uncertain significance ★★ same type
KL p.Ala3Thr Uncertain significance ★★ ⚠ same type
KL p.Ala656Thr Uncertain significance ★★ ⚠ same type
KL p.Ala663Thr Uncertain significance ★★ ⚠ same type
KL p.Ala987Thr Uncertain significance ★★ ⚠ same type
KL p.Arg179Trp Uncertain significance ★★ ⚠ same type
KL p.Arg181Gln Uncertain significance ★★ ⚠ same type
KL p.Arg252His Uncertain significance ★★ ⚠ same type

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-ala50val (accessed [today's date]).

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