Is CAVIN3 p.Glu258Asp (c.774G>C) pathogenic?

CAVIN3 p.Glu258Asp (c.774G>C) is classified Uncertain significance in CAVIN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-06). AlphaMissense: likely benign (0.1148); Ultra-rare (popmax 0.0182%, eas).

How common is CAVIN3 p.Glu258Asp (c.774G>C) in the general population?

CAVIN3 p.Glu258Asp (c.774G>C) is ultra-rare (popmax 0.0182%, eas) (gnomAD).

What do computational predictors say about CAVIN3 p.Glu258Asp (c.774G>C)?

AlphaMissense predicts likely benign (score 0.1148) — an in-silico prediction, not a clinical call.

CAVIN3 p.Glu258Asp

c.774G>C · rs371017691 · VCV2457166

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1148 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0182%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1148	likely benign
REVEL	0.086	moderately benign-leaning
SaProt	LLR -6.82	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 0.79	GERP -2.1, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 1,310 bp · p 0.029 · regional, not allelic
Overall
CADD	19.99	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 0.0182% East Asian · 8/44,050 alleles

Filtering AF 0.0101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00799%

Overall 0.00235% 36/1,529,558 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0238%	4,199
East Asiangrpmax	0.0182%	5,506
South Asian	0.017%	5,870
European (non-Finnish)	8.76e-05%	1,141,918

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CAVIN3
Protein: p.Glu258Asp
Coding: c.774G>C
MANE Select: NM_145040
dbSNP: rs371017691
Type: single nucleotide variant
Location: chr11:6319175 (GRCh38)
Gene constraint: LOEUF 1.958 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.11
Residue 258: the 'disordered' region

Full CAVIN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAVIN3 p.Ala141Ser Uncertain significance ★ ⚠ same type
CAVIN3 p.Ala218Gly Uncertain significance ★ ⚠ same type
CAVIN3 p.Ala220Ser Uncertain significance ★ ⚠ same type
CAVIN3 p.Ala227Val Uncertain significance ★ ⚠ same type
CAVIN3 p.Ala249Ser Uncertain significance ★ ⚠ same type
CAVIN3 p.Ala66Thr Uncertain significance ★ ⚠ same type
CAVIN3 p.Ala94Thr Uncertain significance ★ ⚠ same type
CAVIN3 p.Ala95Val 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/cavin3-p-glu258asp (accessed [today's date]).

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