Is LCK p.Pro57= (c.171G>A) pathogenic?

LCK p.Pro57= (c.171G>A) is classified Benign/Likely benign in LCK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-18). Rare (popmax 0.319%, sas); Associated with severe combined immunodeficiency due to LCK deficiency.

What condition is associated with LCK p.Pro57= (c.171G>A)?

LCK p.Pro57= (c.171G>A) is associated with severe combined immunodeficiency due to LCK deficiency (ClinVar).

How common is LCK p.Pro57= (c.171G>A) in the general population?

LCK p.Pro57= (c.171G>A) is rare (popmax 0.319%, 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.

LCK p.Pro57=

c.171G>A · rs528967735 · VCV474986

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.319%, sas)

Conditions

severe combined immunodeficiency due to LCK deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -4.5
Overall
CADD	6.311	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.319% South Asian · 290/91,036 alleles

Filtering AF 0.288% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.277%

Overall 0.0188% 303/1,613,778 alleles · rare exomes 288/1,461,578 · genomes 15/152,200 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.319%	314
Remaining individualsnot grpmax-eligible	0.016%	6,249
Admixed American	0.00167%	59,964
European (non-Finnish)	0.00017%	589,929

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.Pro57=
Coding: c.171G>A
MANE Select: NM_005356
dbSNP: rs528967735
Type: single nucleotide variant
Location: chr1:32274802 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.12 · 57 PDB
Residue 57: the 'interactions with cd4 and cd8' region

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-pro57 (accessed [today's date]).

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