Is CLVS2 p.Val288Ile (c.862G>A) pathogenic?

CLVS2 p.Val288Ile (c.862G>A) is classified Uncertain significance in CLVS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-14). AlphaMissense: likely benign (0.0657); Very rare (popmax 0.00102%, nfe).

How common is CLVS2 p.Val288Ile (c.862G>A) in the general population?

CLVS2 p.Val288Ile (c.862G>A) is very rare (popmax 0.00102%, nfe) (gnomAD).

What do computational predictors say about CLVS2 p.Val288Ile (c.862G>A)?

AlphaMissense predicts likely benign (score 0.0657) — an in-silico prediction, not a clinical call.

CLVS2 p.Val288Ile

c.862G>A · rs768633966 · VCV2466127

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0657 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0657	likely benign
REVEL	0.213	benign-leaning
SaProt	LLR -6.62	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 5.8	GERP 1.9, phastCons 0.99
Regional constraint	o/e 1.21	unconstrained · MANE · 7,813 bp · p 0.083 · regional, not allelic
Overall
CADD	17.44	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 0.00102% European (non-Finnish) · 12/1,179,832 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000744% 12/1,613,672 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: CLVS2
Protein: p.Val288Ile
Coding: c.862G>A
MANE Select: NM_001010852
dbSNP: rs768633966
Type: single nucleotide variant
Location: chr6:123055992 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.15
Residue 288: the 'disordered' region

Full CLVS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLVS2 p.Ala139Gly Uncertain significance ★ ⚠ same type
CLVS2 p.Ala146Thr Uncertain significance ★ ⚠ same type
CLVS2 p.Arg138Gly Uncertain significance ★ ⚠ same type
CLVS2 p.Arg215Trp Uncertain significance ★ ⚠ same type
CLVS2 p.Arg48Cys Uncertain significance ★ ⚠ same type
CLVS2 p.Asp272Gly Uncertain significance ★ ⚠ same type
CLVS2 p.Glu19Gln Uncertain significance ★ same type
CLVS2 p.Glu316Gly Uncertain significance ★ ⚠ 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/clvs2-p-val288ile (accessed [today's date]).

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