Is LMTK1 p.Ala540Ser (c.1618G>T) pathogenic?

LMTK1 p.Ala540Ser (c.1618G>T) is classified Uncertain significance in LMTK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-14). AlphaMissense: likely benign (0.0955); Very rare (popmax 0.0021%, amr).

How common is LMTK1 p.Ala540Ser (c.1618G>T) in the general population?

LMTK1 p.Ala540Ser (c.1618G>T) is very rare (popmax 0.0021%, amr) (gnomAD).

What do computational predictors say about LMTK1 p.Ala540Ser (c.1618G>T)?

AlphaMissense predicts likely benign (score 0.0955) — an in-silico prediction, not a clinical call.

LMTK1 p.Ala540Ser

c.1618G>T · VCV3829386

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0955 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0021%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0955	likely benign
REVEL	0.193	benign-leaning
SaProt	LLR -6.71	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 -0.16	GERP -2.6
Regional constraint	o/e 1.22	unconstrained · MANE · 4,291 bp · p 2.4e-16 · regional, not allelic
Overall
CADD	4.258	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 0.0021% Admixed American · 1/47,672 alleles

Filtering AF 7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2e-05%

Overall 0.000265% 4/1,508,720 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0021%	47,672
European (non-Finnish)	0.000265%	377,912

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: LMTK1
Protein: p.Ala540Ser
Coding: c.1618G>T
MANE Select: NM_001080395
Type: single nucleotide variant
Location: chr17:81122318 (GRCh38)
Gene constraint: LOEUF 1.574 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.54

Full LMTK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

LMTK1 p.Ala540Val Uncertain significance ★ same residue
LMTK1 p.Ala1020Asp Uncertain significance ★ same type
LMTK1 p.Ala1153Ser Uncertain significance ★ same type
LMTK1 p.Ala1191Val Uncertain significance ★ same type
LMTK1 p.Ala1204Val Uncertain significance ★ same type
LMTK1 p.Ala1367Asp Uncertain significance ★ same type
LMTK1 p.Ala1374Ser Uncertain significance ★ same type
LMTK1 p.Ala193Thr 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/lmtk1-p-ala540ser (accessed [today's date]).

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