Is CITED2 p.Ile233Val (c.697A>G) pathogenic?

CITED2 p.Ile233Val (c.697A>G) is classified Uncertain significance in CITED2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-05). AlphaMissense: likely benign (0.3309); Rare (popmax 0.1%, eas); Associated with ventricular septal defect 2.

What condition is associated with CITED2 p.Ile233Val (c.697A>G)?

CITED2 p.Ile233Val (c.697A>G) is associated with ventricular septal defect 2 (ClinVar).

How common is CITED2 p.Ile233Val (c.697A>G) in the general population?

CITED2 p.Ile233Val (c.697A>G) is rare (popmax 0.1%, eas) (gnomAD).

What do computational predictors say about CITED2 p.Ile233Val (c.697A>G)?

AlphaMissense predicts likely benign (score 0.3309) — an in-silico prediction, not a clinical call.

CITED2 p.Ile233Val

c.697A>G · VCV3779083

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3309 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.1%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ventricular septal defect 2

Computational evidence

Protein change
AlphaMissense	0.3309	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -6.43	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 2.8	GERP -0.24, phastCons 1
Regional constraint	o/e 0.45	unconstrained · MANE · 102 bp · p 0.00024 · regional, not allelic
Overall
CADD	19.52	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 0.1% East Asian · 45/44,888 alleles

Filtering AF 0.077% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0688%

Overall 0.00304% 49/1,614,040 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.1%	998
Remaining individualsnot grpmax-eligible	0.0016%	62,482
African / African-American	0.00133%	74,924
European (non-Finnish)	0.000169%	590,016

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: CITED2
Protein: p.Ile233Val
Coding: c.697A>G
MANE Select: NM_006079
Type: single nucleotide variant
Location: chr6:139373248 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI 0.90 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 52.07 · 4 PDB
Residue 233: an α-helix

Full CITED2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ventricular septal defect 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CITED2 p.Pro130Ser Uncertain significance ★ ⚠ same condition
CITED2 p.196SG[1] Likely benign ★★ same condition
CITED2 p.163GSSTPGGSG[1] Uncertain significance ★ same condition
CITED2 p.Gly180_Ser181insGlySerSerThrProGlyGlySerGly Uncertain significance ★ same condition
CITED2 p.Ala25Pro Uncertain significance ★★ same type
CITED2 p.Ala25Val Uncertain significance ★★ same type
CITED2 p.Pro128Ser Uncertain significance ★★ same type
CITED2 p.Ala7= Benign ★★ 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/cited2-p-ile233val (accessed [today's date]).

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