Is LTK p.Arg376Pro (c.1127G>C) pathogenic?

LTK p.Arg376Pro (c.1127G>C) is classified Uncertain significance in LTK (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-28). AlphaMissense: likely pathogenic (0.7688); Very rare (popmax 0.00636%, nfe).

How common is LTK p.Arg376Pro (c.1127G>C) in the general population?

LTK p.Arg376Pro (c.1127G>C) is very rare (popmax 0.00636%, nfe) (gnomAD).

What do computational predictors say about LTK p.Arg376Pro (c.1127G>C)?

AlphaMissense predicts likely pathogenic (score 0.7688) — an in-silico prediction, not a clinical call.

LTK p.Arg376Pro

c.1127G>C · rs150610943 · VCV2600168

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7688 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00636%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7688	likely pathogenic
REVEL	0.42	indeterminate
SaProt	LLR -10.77	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3.7	GERP -1.7
Regional constraint	o/e 1.07	unconstrained · MANE · 9,710 bp · p 0.011 · regional, not allelic
Overall
CADD	16.18	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 0.00636% European (non-Finnish) · 75/1,179,352 alleles

Filtering AF 0.00519% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00474%

Overall 0.00471% 76/1,612,402 alleles · very rare exomes 65/1,460,504 · genomes 11/151,898 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00636%	15,725
African / African-American	0.00134%	74,742

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.Arg376Pro
Coding: c.1127G>C
MANE Select: NM_002344
dbSNP: rs150610943
Type: single nucleotide variant
Location: chr15:41508191 (GRCh38)
Gene constraint: LOEUF 1.42 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.41 · 2 PDB
Residue 376: a β-strand

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

Similar variants

LTK p.Arg376Gly Uncertain significance ★ ⚠ same residue
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

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-arg376pro (accessed [today's date]).

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