Is LTK p.Ala321Asp (c.962C>A) pathogenic?

LTK p.Ala321Asp (c.962C>A) is classified Uncertain significance in LTK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: likely pathogenic (0.7045); Very rare (popmax 9.25e-05%, nfe).

How common is LTK p.Ala321Asp (c.962C>A) in the general population?

LTK p.Ala321Asp (c.962C>A) is very rare (popmax 9.25e-05%, nfe) (gnomAD).

What do computational predictors say about LTK p.Ala321Asp (c.962C>A)?

AlphaMissense predicts likely pathogenic (score 0.7045) — an in-silico prediction, not a clinical call.

LTK p.Ala321Asp

c.962C>A · VCV4101411

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7045 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 9.25e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7045	likely pathogenic
REVEL	0.495	indeterminate
SaProt	LLR -6.03	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.3	GERP -2.8, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 9,710 bp · p 0.011 · regional, not allelic
Overall
CADD	20.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.25e-05% European (non-Finnish) · 1/1,081,346 alleles

Overall 7.17e-05% 1/1,394,746 alleles · very rare exomes 1/1,243,366 · genomes 0/151,380 · 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: LTK
Protein: p.Ala321Asp
Coding: c.962C>A
MANE Select: NM_002344
Type: single nucleotide variant
Location: chr15:41511199 (GRCh38)
Gene constraint: LOEUF 1.42 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.41 · 2 PDB
Residue 321: an α-helix

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

Similar variants

LTK p.Ala321Val 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-ala321asp (accessed [today's date]).

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