Is ICOS p.Lys43Arg (c.128A>G) pathogenic?

ICOS p.Lys43Arg (c.128A>G) is classified Uncertain significance in ICOS (ClinVar, Single submitter, 1 submitter; last evaluated 2019-11-06). AlphaMissense: likely benign (0.0847); Very rare (popmax 0.000254%, nfe); Associated with immunodeficiency, common variable, 1.

What condition is associated with ICOS p.Lys43Arg (c.128A>G)?

ICOS p.Lys43Arg (c.128A>G) is associated with immunodeficiency, common variable, 1 (ClinVar).

How common is ICOS p.Lys43Arg (c.128A>G) in the general population?

ICOS p.Lys43Arg (c.128A>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about ICOS p.Lys43Arg (c.128A>G)?

AlphaMissense predicts likely benign (score 0.0847) — an in-silico prediction, not a clinical call.

ICOS p.Lys43Arg

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.128A>G · rs1367837109 · VCV960748

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0847 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency, common variable, 1

Computational evidence

Protein change
AlphaMissense	0.0847	likely benign
REVEL	0.024	moderately benign-leaning
SaProt	LLR -7.28	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 1.3	GERP -0.79, phastCons 0.99
Regional constraint	o/e 0.86	unconstrained · MANE · 23 kb · p 0.03 · regional, not allelic
Overall
CADD	15.71	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

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,692 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,432 alleles · very rare

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.Lys43Arg
Coding: c.128A>G
MANE Select: NM_012092
dbSNP: rs1367837109
Type: single nucleotide variant
Location: chr2:203955705 (GRCh38)
Gene constraint: LOEUF 1.273 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.24 · 2 PDB
Residue 43: 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.Lys43Asn 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
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-lys43arg (accessed [today's date]).

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