Is LCK p.Arg461Ser (c.1381C>A) pathogenic?

LCK p.Arg461Ser (c.1381C>A) is classified Uncertain significance in LCK (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-23). AlphaMissense: ambiguous (0.3803); Very rare (popmax 0.00167%, amr).

How common is LCK p.Arg461Ser (c.1381C>A) in the general population?

LCK p.Arg461Ser (c.1381C>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about LCK p.Arg461Ser (c.1381C>A)?

AlphaMissense predicts ambiguous (score 0.3803) — an in-silico prediction, not a clinical call.

LCK p.Arg461Ser

c.1381C>A · rs773475751 · VCV2477421

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3803 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Computational evidence

Protein change
AlphaMissense	0.3803	ambiguous
REVEL	0.364	indeterminate
SaProt	LLR -8.03	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.004	GERP -4.4
Regional constraint	o/e 0.53	unconstrained · MANE · 9,339 bp · p 1.3e-19 · regional, not allelic
Overall
CADD	6.436	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 0.00167% Admixed American · 1/60,024 alleles

Overall 6.84e-05% 1/1,461,884 alleles · very rare

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: LCK
Protein: p.Arg461Ser
Coding: c.1381C>A
MANE Select: NM_005356
dbSNP: rs773475751
Type: single nucleotide variant
Location: chr1:32285567 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.12 · 57 PDB
Residue 461: an α-helix; the protein kinase domain

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

Similar variants

LCK p.Arg461His Uncertain significance ★★ ⚠ same residue
LCK p.Arg461= Likely benign ★ same residue
LCK p.Arg461Cys Likely benign ★ same residue
LCK c.631+3G>A Uncertain significance ★★ same type
LCK p.Ala284Gly Uncertain significance ★★ ⚠ same type
LCK p.Arg196Pro Uncertain significance ★★ ⚠ same type
LCK p.Arg219Gln Uncertain significance ★★ ⚠ same type
LCK p.Arg222His 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/lck-p-arg461ser (accessed [today's date]).

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