Is KLK4 p.Cys148Phe (c.443G>T) pathogenic?

KLK4 p.Cys148Phe (c.443G>T) is classified Uncertain significance in KLK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-01). AlphaMissense: likely pathogenic (0.9421); Absent from gnomAD v4.1; Associated with amelogenesis imperfecta type 2A1.

What condition is associated with KLK4 p.Cys148Phe (c.443G>T)?

KLK4 p.Cys148Phe (c.443G>T) is associated with amelogenesis imperfecta type 2A1 (ClinVar).

How common is KLK4 p.Cys148Phe (c.443G>T) in the general population?

KLK4 p.Cys148Phe (c.443G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about KLK4 p.Cys148Phe (c.443G>T)?

AlphaMissense predicts likely pathogenic (score 0.9421) — an in-silico prediction, not a clinical call.

KLK4 p.Cys148Phe

c.443G>T · rs143632081 · VCV2445594

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9421 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

amelogenesis imperfecta type 2A1

Computational evidence

Protein change
AlphaMissense	0.9421	likely pathogenic
REVEL	0.715	pathogenic-leaning
SaProt	LLR -13.97	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 1.4, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 3,801 bp · p 0.36 · regional, not allelic
Overall
CADD	25.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: KLK4
Protein: p.Cys148Phe
Coding: c.443G>T
MANE Select: NM_004917
dbSNP: rs143632081
Type: single nucleotide variant
Location: chr19:50908611 (GRCh38)
Gene constraint: LOEUF 1.467 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.60 · 18 PDB
Residue 148: a disulfide bond; the peptidase s1 domain; a β-strand

Full KLK4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

amelogenesis imperfecta type 2A1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KLK4 p.Cys148Tyr Uncertain significance ★ ⚠ same residue
KLK4 p.Trp153Ter Pathogenic/Likely pathogenic ★★ same condition
KLK4 c.224+2T>C Likely pathogenic ★ same condition
KLK4 p.Leu211fs Pathogenic ★★ same condition
KLK4 p.Ser207fs Likely pathogenic ★ same condition
KLK4 p.Gly82fs Pathogenic same condition
KLK4 p.Pro227Leu Uncertain significance ★★ ⚠ same type
KLK4 c.224+182G>C Benign ★★ 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/klk4-p-cys148phe (accessed [today's date]).

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