Is ICOS p.His129= (c.387T>C) pathogenic?

ICOS p.His129= (c.387T>C) is classified Likely benign in ICOS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-14). Absent from gnomAD v4.1; Associated with immunodeficiency, common variable, 1.

What condition is associated with ICOS p.His129= (c.387T>C)?

ICOS p.His129= (c.387T>C) is associated with immunodeficiency, common variable, 1 (ClinVar).

How common is ICOS p.His129= (c.387T>C) in the general population?

ICOS p.His129= (c.387T>C) is absent from gnomAD v4.1 (gnomAD).

ICOS p.His129=

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.387T>C · rs2469807475 · VCV2797046

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,603,078)

Conditions

immunodeficiency, common variable, 1

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 5.1	GERP 1.8, phastCons 1
Overall
CADD	9.718	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,603,078). 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: ICOS
Protein: p.His129=
Coding: c.387T>C
MANE Select: NM_012092
dbSNP: rs2469807475
Type: single nucleotide variant
Location: chr2:203955964 (GRCh38)
Gene constraint: LOEUF 1.273 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.24 · 2 PDB
Residue 129: the ig-like v-type domain

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 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
ICOS p.Ser171Tyr Uncertain significance ★★ ⚠ same condition
ICOS p.Thr195Ile 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-his129 (accessed [today's date]).

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