Is LTK p.Arg658Pro (c.1973G>C) pathogenic?

LTK p.Arg658Pro (c.1973G>C) is classified Uncertain significance in LTK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: likely pathogenic (0.7227); Rare (popmax 0.127%, eas).

How common is LTK p.Arg658Pro (c.1973G>C) in the general population?

LTK p.Arg658Pro (c.1973G>C) is rare (popmax 0.127%, eas) (gnomAD).

What do computational predictors say about LTK p.Arg658Pro (c.1973G>C)?

AlphaMissense predicts likely pathogenic (score 0.7227) — an in-silico prediction, not a clinical call.

LTK p.Arg658Pro

c.1973G>C · rs367918796 · VCV3121490

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7227 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.127%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7227	likely pathogenic
REVEL	0.56	indeterminate
SaProt	LLR -13.18	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.48	GERP 0.52
Regional constraint	o/e 1.07	unconstrained · MANE · 9,710 bp · p 0.011 · regional, not allelic
Overall
CADD	23.0	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 0.127% East Asian · 57/44,884 alleles

Filtering AF 0.101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0912%

Overall 0.00496% 80/1,613,408 alleles · rare exomes 75/1,461,228 · genomes 5/152,180 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.127%	787
South Asian	0.0176%	5,690
Remaining individualsnot grpmax-eligible	0.008%	12,492
Admixed American	0.00334%	29,959

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: LTK
Protein: p.Arg658Pro
Coding: c.1973G>C
MANE Select: NM_002344
dbSNP: rs367918796
Type: single nucleotide variant
Location: chr15:41505017 (GRCh38)
Gene constraint: LOEUF 1.42 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.41 · 2 PDB
Residue 658: the protein kinase domain

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

Similar variants

LTK p.Arg569Ser Benign ★★ same type
LTK p.Glu813Ter Likely benign ★★ same type
LTK p.Ala139Thr Uncertain significance ★ ⚠ same type
LTK p.Ala13Thr Uncertain significance ★ ⚠ same type
LTK p.Ala14Ser Uncertain significance ★ ⚠ same type
LTK p.Ala250Val Uncertain significance ★ ⚠ same type
LTK p.Ala305Val Uncertain significance ★ ⚠ same type
LTK p.Ala321Asp 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/ltk-p-arg658pro (accessed [today's date]).

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