Is ICOS p.Ile145Val (c.433A>G) pathogenic?

ICOS p.Ile145Val (c.433A>G) is classified Uncertain significance in ICOS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: likely benign (0.0634); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with ICOS p.Ile145Val (c.433A>G)?

ICOS p.Ile145Val (c.433A>G) is associated with Inborn genetic diseases (ClinVar).

How common is ICOS p.Ile145Val (c.433A>G) in the general population?

ICOS p.Ile145Val (c.433A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ICOS p.Ile145Val (c.433A>G)?

AlphaMissense predicts likely benign (score 0.0634) — an in-silico prediction, not a clinical call.

ICOS p.Ile145Val

c.433A>G · VCV4834829

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0634 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0634	likely benign
REVEL	0.024	moderately benign-leaning
SaProt	LLR -5.92	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.32	GERP -0.66
Regional constraint	o/e 0.86	unconstrained · MANE · 23 kb · p 0.03 · regional, not allelic
Overall
CADD	12.31	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

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.Ile145Val
Coding: c.433A>G
MANE Select: NM_012092
Type: single nucleotide variant
Location: chr2:203956697 (GRCh38)
Gene constraint: LOEUF 1.273 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.24 · 2 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ICOS p.Gln134Pro Uncertain significance ★★ ⚠ same condition
ICOS p.Ile77Val Uncertain significance ★★ ⚠ same condition
ICOS p.Lys167Met Uncertain significance ★★ ⚠ same condition
ICOS p.Thr195Ile Uncertain significance ★★ ⚠ same condition
ICOS p.Ala104Val Uncertain significance ★ ⚠ same condition
ICOS p.Asn98Asp Uncertain significance ★ ⚠ same condition
ICOS p.Gln60Lys Uncertain significance ★ ⚠ same condition
ICOS p.Gly58Ala 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-ile145val (accessed [today's date]).

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