Is ZAP70 p.Pro508= (c.1524C>T) pathogenic?

ZAP70 p.Pro508= (c.1524C>T) is classified Likely benign in ZAP70 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-20). Very rare (popmax 0.00333%, amr); Associated with combined immunodeficiency due to ZAP70 deficiency.

What condition is associated with ZAP70 p.Pro508= (c.1524C>T)?

ZAP70 p.Pro508= (c.1524C>T) is associated with combined immunodeficiency due to ZAP70 deficiency (ClinVar).

How common is ZAP70 p.Pro508= (c.1524C>T) in the general population?

ZAP70 p.Pro508= (c.1524C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

ZAP70 p.Pro508=

Q: How is Combined immunodeficiency due to ZAP70 deficiency inherited?

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

c.1524C>T · rs1291542609 · VCV1093131

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

combined immunodeficiency due to ZAP70 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -15	GERP -3.6
Overall
CADD	2.395	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,990 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000805% 13/1,614,004 alleles · very rare exomes 11/1,461,848 · genomes 2/152,156 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,995
South Asian	0.0011%	91,086
European (non-Finnish)	0.000847%	118,000

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: ZAP70
Protein: p.Pro508=
Coding: c.1524C>T
MANE Select: NM_001079
dbSNP: rs1291542609
Type: single nucleotide variant
Location: chr2:97737798 (GRCh38)
Gene constraint: LOEUF 0.624 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.91 · 15 PDB
Residue 508: an α-helix; the protein kinase domain

Full ZAP70 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

combined immunodeficiency due to ZAP70 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Combined immunodeficiency due to ZAP70 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

ZAP70 c.1624-11G>A Pathogenic ★★ same condition
ZAP70 p.Arg37Gly Pathogenic/Likely pathogenic ★★ same condition
ZAP70 p.Arg465Cys Likely pathogenic ★★ same condition
ZAP70 c.1083-3C>A Uncertain significance ★★ same condition
ZAP70 c.403-3T>C Uncertain significance ★★ same condition
ZAP70 c.790+6G>A Uncertain significance ★★ same condition
ZAP70 c.837+6T>C Uncertain significance ★★ same condition
ZAP70 c.889+6C>T 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/zap70-p-pro508 (accessed [today's date]).

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