Is ZAP70 p.Pro110Ser (c.328C>T) pathogenic?

ZAP70 p.Pro110Ser (c.328C>T) is classified Uncertain significance in ZAP70 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-04). AlphaMissense: ambiguous (0.4398); No allele count reported in gnomAD v4.1 (AN 1,547,368); Associated with combined immunodeficiency due to ZAP70 deficiency.

What condition is associated with ZAP70 p.Pro110Ser (c.328C>T)?

ZAP70 p.Pro110Ser (c.328C>T) is associated with combined immunodeficiency due to ZAP70 deficiency (ClinVar).

How common is ZAP70 p.Pro110Ser (c.328C>T) in the general population?

ZAP70 p.Pro110Ser (c.328C>T) is no allele count reported in gnomAD v4.1 (AN 1,547,368) (gnomAD).

What do computational predictors say about ZAP70 p.Pro110Ser (c.328C>T)?

AlphaMissense predicts ambiguous (score 0.4398) — an in-silico prediction, not a clinical call.

ZAP70 p.Pro110Ser

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.328C>T · rs1353682044 · VCV1398656

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4398 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,547,368)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

combined immunodeficiency due to ZAP70 deficiency

Computational evidence

Protein change
AlphaMissense	0.4398	ambiguous
REVEL	0.063	moderately benign-leaning
SaProt	LLR -8.17	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.2	GERP 1.7, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 13 kb · p 0.0017 · regional, not allelic
Overall
CADD	20.8	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

No allele count reported in gnomAD v4.1 (AN 1,547,368). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: ZAP70
Protein: p.Pro110Ser
Coding: c.328C>T
MANE Select: NM_001079
dbSNP: rs1353682044
Type: single nucleotide variant
Location: chr2:97724364 (GRCh38)
Gene constraint: LOEUF 0.624 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.91 · 15 PDB
Residue 110: the 'interdomain a' region; an α-helix

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 p.Pro110= Likely benign ★ same residue
ZAP70 p.Pro110Leu Uncertain significance ★★ ⚠ same residue
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

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-pro110ser (accessed [today's date]).

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