Is LCK p.Thr431Met (c.1292C>T) pathogenic?

LCK p.Thr431Met (c.1292C>T) is classified Uncertain significance in LCK (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-01). AlphaMissense: likely benign (0.1739); Ultra-rare (popmax 0.0845%, sas); Associated with severe combined immunodeficiency due to LCK deficiency.

What condition is associated with LCK p.Thr431Met (c.1292C>T)?

LCK p.Thr431Met (c.1292C>T) is associated with severe combined immunodeficiency due to LCK deficiency (ClinVar).

How common is LCK p.Thr431Met (c.1292C>T) in the general population?

LCK p.Thr431Met (c.1292C>T) is ultra-rare (popmax 0.0845%, sas) (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.Thr431Met (c.1292C>T)?

AlphaMissense predicts likely benign (score 0.1739) — an in-silico prediction, not a clinical call.

LCK p.Thr431Met

c.1292C>T · rs1801124 · VCV1018077

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1739 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0845%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

severe combined immunodeficiency due to LCK deficiency

Computational evidence

Protein change
AlphaMissense	0.1739	likely benign
REVEL	0.567	indeterminate
SaProt	LLR -10.16	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.8, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 9,339 bp · p 1.3e-19 · regional, not allelic
Overall
CADD	24.6	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 0.0845% South Asian · 77/91,082 alleles

Filtering AF 0.0693% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0637%

Overall 0.0107% 173/1,614,092 alleles · ultra-rare exomes 156/1,461,888 · genomes 17/152,204 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0845%	1,183
Remaining individualsnot grpmax-eligible	0.024%	4,167
Admixed American	0.0167%	6,000
Middle Eastern	0.0165%	6,062
Finnishnot grpmax-eligible	0.0156%	6,402
African / African-American	0.00666%	15,004
European (non-Finnish)	0.00466%	21,455

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.Thr431Met
Coding: c.1292C>T
MANE Select: NM_005356
dbSNP: rs1801124
Type: single nucleotide variant
Location: chr1:32280175 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.12 · 57 PDB
Residue 431: the protein kinase domain; an α-helix

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 p.Thr431= Likely benign ★ same residue
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

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-thr431met (accessed [today's date]).

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