Is CTLA4 p.Ile166Val (c.496A>G) pathogenic?

CTLA4 p.Ile166Val (c.496A>G) is classified Uncertain significance in CTLA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-26). AlphaMissense: likely benign (0.0851); Very rare (popmax 0.00223%, eas).

How common is CTLA4 p.Ile166Val (c.496A>G) in the general population?

CTLA4 p.Ile166Val (c.496A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CTLA4 p.Ile166Val (c.496A>G)?

AlphaMissense predicts likely benign (score 0.0851) — an in-silico prediction, not a clinical call.

CTLA4 p.Ile166Val

c.496A>G · rs779775271 · VCV1326454

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0851 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0851	likely benign
REVEL	0.01	strongly benign-leaning
SaProt	LLR -6.16	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.25	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 1.6	GERP -0.76, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 2,198 bp · p 3.2e-07 · regional, not allelic
Overall
CADD	16.29	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 0.00223% East Asian · 1/44,870 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00185% 27/1,461,888 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,870
European (non-Finnish)	0.00212%	47,201
Remaining individualsnot grpmax-eligible	0.0016%	62,508

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: CTLA4
Protein: p.Ile166Val
Coding: c.496A>G
MANE Select: NM_005214
dbSNP: rs779775271
Type: single nucleotide variant
Location: chr2:203871416 (GRCh38)
Gene constraint: LOEUF 0.211 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.67 · 22 PDB

Full CTLA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CTLA4 p.Ile166Asn Uncertain significance ★ ⚠ same residue
CTLA4 p.Ile166Thr Uncertain significance ★ ⚠ same residue
CTLA4 p.Arg51Ter Pathogenic ★★★ same type
CTLA4 p.Arg75Trp Pathogenic ★★★ ⚠ same type
CTLA4 p.Asp153Asn Pathogenic ★★★ ⚠ same type
CTLA4 p.Cys35Ter Pathogenic ★★★ same type
CTLA4 p.Pro136Ala Likely pathogenic ★★★ same type
CTLA4 p.Pro136Leu Likely pathogenic ★★★ same type

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/ctla4-p-ile166val (accessed [today's date]).

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