Is LCK p.Pro440Ser (c.1318C>T) pathogenic?

LCK p.Pro440Ser (c.1318C>T) is classified Pathogenic in LCK (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-03-26). AlphaMissense: likely pathogenic (0.9994); Very rare (popmax 8.47e-05%, nfe); Associated with severe combined immunodeficiency due to LCK deficiency.

What condition is associated with LCK p.Pro440Ser (c.1318C>T)?

LCK p.Pro440Ser (c.1318C>T) is associated with severe combined immunodeficiency due to LCK deficiency (ClinVar).

How common is LCK p.Pro440Ser (c.1318C>T) in the general population?

LCK p.Pro440Ser (c.1318C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Combined immunodeficiency due to LCK deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about LCK p.Pro440Ser (c.1318C>T)?

AlphaMissense predicts likely pathogenic (score 0.9994) — an in-silico prediction, not a clinical call.

LCK p.Pro440Ser

c.1318C>T · rs1318678254 · VCV3064214

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9994 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

severe combined immunodeficiency due to LCK deficiency

Computational evidence

Protein change
AlphaMissense	0.9994	likely pathogenic ✓ concordant with ClinVar · top 5% in LCK
REVEL	0.91	moderately pathogenic-leaning
SaProt	LLR -11.37	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 2.8, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 9,339 bp · p 1.3e-19 · regional, not allelic
Overall
CADD	29.9	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 8.47e-05% European (non-Finnish) · 1/1,180,024 alleles

Overall 6.2e-05% 1/1,613,986 alleles · very rare exomes 0/1,461,876 · genomes 1/152,110 · 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: LCK
Protein: p.Pro440Ser
Coding: c.1318C>T
MANE Select: NM_005356
dbSNP: rs1318678254
Type: single nucleotide variant
Location: chr1:32280201 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.12 · 57 PDB
Residue 440: the protein kinase domain

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

Disease context

severe combined immunodeficiency due to LCK deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Combined immunodeficiency due to LCK deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

LCK c.631+3G>A Uncertain significance ★★ same condition
LCK p.Ala284Gly Uncertain significance ★★ ⚠ same condition
LCK p.Arg196Pro Uncertain significance ★★ ⚠ same condition
LCK p.Arg219Gln Uncertain significance ★★ ⚠ same condition
LCK p.Arg222His Uncertain significance ★★ ⚠ same condition
LCK p.Arg461His Uncertain significance ★★ ⚠ same condition
LCK p.Asn40Ser Uncertain significance ★★ ⚠ same condition
LCK p.Asp187Gly Uncertain significance ★★ ⚠ same condition

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-pro440ser (accessed [today's date]).

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