Is ICOS p.Cys63Ter (c.189C>A) pathogenic?

ICOS p.Cys63Ter (c.189C>A) is classified Conflicting classifications of pathogenicity in ICOS (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-23). Absent from gnomAD v4.1; Associated with immunodeficiency, common variable, 1.

What condition is associated with ICOS p.Cys63Ter (c.189C>A)?

ICOS p.Cys63Ter (c.189C>A) is associated with immunodeficiency, common variable, 1 (ClinVar).

How common is ICOS p.Cys63Ter (c.189C>A) in the general population?

ICOS p.Cys63Ter (c.189C>A) is absent from gnomAD v4.1 (gnomAD).

ICOS p.Cys63Ter

Q: How is Late-onset combined immunodeficiency due to ICOS deficiency inherited?

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

c.189C>A · rs537195517 · VCV666602

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

immunodeficiency, common variable, 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 5
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.72	GERP -0.94, phastCons 1
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ICOS
Protein: p.Cys63Ter
Coding: c.189C>A
MANE Select: NM_012092
dbSNP: rs537195517
Type: single nucleotide variant
Location: chr2:203955766 (GRCh38)
Gene constraint: LOEUF 1.273 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.24 · 2 PDB
Residue 63: a β-strand; the ig-like v-type domain; a disulfide bond

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

Disease context

immunodeficiency, common variable, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Late-onset combined immunodeficiency due to ICOS deficiency (Orphanet):

Inheritance: Autosomal recessive

Similar variants

ICOS p.Cys63= Likely benign ★ same residue
ICOS p.Cys63Tyr Uncertain significance ★ ⚠ same residue
ICOS c.58+1G>A Likely pathogenic ★★ same condition
ICOS c.59-3C>T Uncertain significance ★★ same condition
ICOS p.Gln134Pro Uncertain significance ★★ ⚠ same condition
ICOS p.Gly24Val Uncertain significance ★★ ⚠ same condition
ICOS p.Gly36Arg Uncertain significance ★★ ⚠ same condition
ICOS p.Ile77Val 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/icos-p-cys63ter (accessed [today's date]).

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