Is ICOS p.Phe119Ser (c.356T>C) pathogenic?

ICOS p.Phe119Ser (c.356T>C) is classified Conflicting classifications of pathogenicity in ICOS (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-05-19). AlphaMissense: ambiguous (0.4932); Ultra-rare (popmax 0.0113%, nfe); Associated with Inherited Immunodeficiency Diseases.

What condition is associated with ICOS p.Phe119Ser (c.356T>C)?

ICOS p.Phe119Ser (c.356T>C) is associated with Inherited Immunodeficiency Diseases, immunodeficiency, common variable, 1 (ClinVar).

How common is ICOS p.Phe119Ser (c.356T>C) in the general population?

ICOS p.Phe119Ser (c.356T>C) is ultra-rare (popmax 0.0113%, nfe) (gnomAD).

What do computational predictors say about ICOS p.Phe119Ser (c.356T>C)?

AlphaMissense predicts ambiguous (score 0.4932) — an in-silico prediction, not a clinical call.

ICOS p.Phe119Ser

c.356T>C · rs375299065 · VCV827707

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4932 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0113%, nfe)

Conditions

Inherited Immunodeficiency Diseases

Computational evidence

Protein change
AlphaMissense	0.4932	ambiguous
REVEL	0.604	indeterminate
SaProt	LLR -10.71	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP -3.1, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 23 kb · p 0.03 · regional, not allelic
Overall
CADD	23.0	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

Grpmax group 0.0113% European (non-Finnish) · 133/1,178,804 alleles

Filtering AF 0.0097% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00906%

Overall 0.00825% 133/1,612,342 alleles · ultra-rare exomes 130/1,460,162 · genomes 3/152,180 · joint denominator

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: ICOS
Protein: p.Phe119Ser
Coding: c.356T>C
MANE Select: NM_012092
dbSNP: rs375299065
Type: single nucleotide variant
Location: chr2:203955933 (GRCh38)
Gene constraint: LOEUF 1.273 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.24 · 2 PDB
Residue 119: the ig-like v-type domain

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

Disease context

Inherited Immunodeficiency Diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: immunodeficiency, common variable, 1

Similar variants

ICOS p.Phe119fs Pathogenic ★ 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
ICOS p.Ser171Tyr 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-phe119ser (accessed [today's date]).

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