Is LMTK3 p.Pro559Ser (c.1675C>T) pathogenic?

LMTK3 p.Pro559Ser (c.1675C>T) is classified Uncertain significance in LMTK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: likely benign (0.2672); Very rare (popmax 0.00136%, nfe).

How common is LMTK3 p.Pro559Ser (c.1675C>T) in the general population?

LMTK3 p.Pro559Ser (c.1675C>T) is very rare (popmax 0.00136%, nfe) (gnomAD).

What do computational predictors say about LMTK3 p.Pro559Ser (c.1675C>T)?

AlphaMissense predicts likely benign (score 0.2672) — an in-silico prediction, not a clinical call.

LMTK3 p.Pro559Ser

c.1675C>T · VCV4098793

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2672 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2672	likely benign
REVEL	0.192	benign-leaning
SaProt	LLR -6.90	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 6.8	GERP -0.54, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 2,169 bp · p 0.48 · regional, not allelic
Overall
CADD	24.3	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 0.00136% European (non-Finnish) · 15/1,099,320 alleles

Filtering AF 0.000819% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00104% 15/1,448,198 alleles · very rare exomes 14/1,296,170 · genomes 1/152,028 · 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: LMTK3
Protein: p.Pro559Ser
Coding: c.1675C>T
MANE Select: NM_001388485
Type: single nucleotide variant
Location: chr19:48499394 (GRCh38)
Gene constraint: LOEUF 0.517 · pLI 0.89 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 47.17 · 1 PDB
Residue 559: the 'disordered' region

Full LMTK3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

LMTK3 p.Pro559Arg Uncertain significance ★ ⚠ same residue
LMTK3 p.Leu314= Benign ★★ same type
LMTK3 p.Leu354= Benign ★★ same type
LMTK3 p.Pro22= Likely benign ★★ same type
LMTK3 c.-35G>T Uncertain significance ★ same type
LMTK3 c.-44G>A Uncertain significance ★ same type
LMTK3 c.-45C>T Uncertain significance ★ same type
LMTK3 c.-6G>T 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/lmtk3-p-pro559ser (accessed [today's date]).

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