Is ICOS p.Phe31= (c.93T>C) pathogenic?

ICOS p.Phe31= (c.93T>C) is classified Likely benign in ICOS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-05). Ultra-rare (popmax 0.033%, mid); Associated with immunodeficiency, common variable, 1.

What condition is associated with ICOS p.Phe31= (c.93T>C)?

ICOS p.Phe31= (c.93T>C) is associated with immunodeficiency, common variable, 1 (ClinVar).

How common is ICOS p.Phe31= (c.93T>C) in the general population?

ICOS p.Phe31= (c.93T>C) is ultra-rare (popmax 0.033%, mid) (gnomAD).

ICOS p.Phe31=

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.93T>C · rs147754976 · VCV788962

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

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 0.048	GERP -2.3, phastCons 0.005
Overall
CADD	7.089	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,056 alleles

Filtering AF 0.00722% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.00713% 115/1,613,546 alleles · ultra-rare exomes 100/1,461,238 · genomes 15/152,308 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,028
African / African-American	0.0133%	7,503
European (non-Finnish)	0.00814%	12,287
South Asian	0.00329%	30,357
East Asian	0.00223%	44,848
Admixed American	0.00167%	59,996
Remaining individualsnot grpmax-eligible	0.0016%	62,478
Finnishnot grpmax-eligible	0.00156%	64,036

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.Phe31=
Coding: c.93T>C
MANE Select: NM_012092
dbSNP: rs147754976
Type: single nucleotide variant
Location: chr2:203955670 (GRCh38)
Gene constraint: LOEUF 1.273 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.24 · 2 PDB
Residue 31: a β-strand; 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-phe31 (accessed [today's date]).

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